Protein having multiple antigen/epitope sequences and being immobilized

ABSTRACT

The invention relates to a protein having multiple antigen/epitope sequences for antibodies, wherein the protein is immobilized at a solid phase by at least one binding site, and the antigen/epitope sequences are spaced by bridge compositions in such a way that after binding of the binding site at the solid phase the antigen/epitope sequences are exposed for a binding of the assigned antibodies from the liquid phase.

FIELD OF THE INVENTION

[0001] The invention relates to a protein having multiple antigen/epitope sequences and being immobilized, to a polynucleotide coding for such a protein, to an expression vector including such polynucleotide, to a cell transformed by means of such an expression vector, and to applications of such a protein for producing an immobilizate and for performing a HIV test.

BACKGROUND OF THE INVENTION

[0002] Immobilizates comprising a solid phase and one or more proteins bound to the solid phase are well known by practical experiences. Such immobilizates are used, on one hand, for the detection of substances of a liquid analyzate specifically binding to the protein, and on the other hand for the separation of such substances from a liquid. Therein the protein comprises an epitope being specific for the substance to be detected or to be separated, and this epitope normally binds to the solid phase by a spacer composition per se not binding to the substance. The spacer composition secures, among other effects, that the protein folds in the area of the epitope in a way corresponding to the folding of a native epitope. This, i.e. the desired exposure of the epitope, is the condition for that a binding of the substance is at all possible. In particular, the formation of undesired disulfide bridges is prevented.

[0003] In some fields of medicine, it is desirable that various epitopes are immobilized at the same time at the solid phase. This is desirable, for instance, in the case of HIV tests, since only an accumulation of epitopes being specific for antibodies for various HIV1 and HIV2 viruses and sub-types will secure a reliable decision on the basis of the test result about whether or not the tested sample contains HIV antibodies, i.e. whether or not a person is HIV positive.

[0004] In principle, the respective proteins, for instance antigens against various HIV antibodies, could be immobilized each for its own at the solid phase. This presents however various problems. The first problem is that a uniform distribution of the proteins, in particular with regard to concentrations, and thus a sufficiently uniform sensitivity for the various antibodies cannot be secured. For various proteins may lead to ousting reactions at the solid phase, with the consequence of substantially disturbing concentration differences at the solid phase, even with equimolar addition. Further, with a higher multitude of different proteins, interactions of the various proteins during immobilization cannot be excluded. All this will disturb, however, if a universal test, for instance for HIV, is to be established. The above will apply in a corresponding manner, of course, to all diseases causing, depending from the classes and sub-types of the infecting organism, immunologically distinguishable antibodies in a body. It is understood that different antibodies against a specific sub-type may also be formed.

[0005] In conjunction with HIV, the following is to be noted. The acquired immunodeficiency syndrome (AIDS) is caused by the HIV. The two causative types HIV-1 and HIV-2 detected up to now have a very similar genome structure and infect T cells using a very similar mechanism. They immunologically differ, however, by that antibodies against HIV-1 do not usually present a cross reaction with HIV-2, and vice versa. For HIV-1, further, a series of sub-types are distinguished, with the group M comprising several sub-types (A, B, C, D, E, F and G), and the sub-type 0 being classified in an own group (0). Even between the antibodies against different sub-types there are immunological differences. It is difficult, therefore, to reliably detect in a single test system all sub-types or antibodies thereagainst. This particularly applies to rapid tests having to be performed without too large experimental expenses. In a rapid test, a reliable result should be obtainable with a single application for instance of a blood sample. In particular in conjunction with HIV, incorrect negative and incorrect positive results must virtually be impossible.

[0006] State of the Art

[0007] Exemplary for the application of one or more antigens in a mixture against various HIV antibodies is the document U.S. Pat. No. 5,830,641.

[0008] Rapid tests known up to now usually operate, however, with one single antigen, namely gp41, and are not capable, therefore, to detect all HIV sub-types reliably and at high sensitivity. There is thus a substantial risk of incorrect negative results. Further, they are not temperature-stable over longer periods of time, not suitable for permanent documentation, do not secure a simple and safe disposal, and present an incorrect positive result in case of over-development.

[0009] Fusion proteins having more than one epitope for HIV antibodies are per se known in the art, for instance from the documents U.S. Pat. Nos. 5,800,822 and 5,310,876. These are proteins used in a solution for laboratory tests. Such laboratory test systems are not suitable, however, for rapid tests, due to the complicated handling and the high risk of incorrect results during execution caused by not properly educated persons.

[0010] From the document U.S. Pat. No. 4,925,784 is known a fusion protein gag/env which may also be immobilized. Bridge compositions with binding sites for a binding with a solid phase between gag and env cannot be taken out. The fusion protein binds at one side over a bridge to a solid phase.

[0011] From the document DE 197 20 914 A1 are known in the art various antigens against antibodies of different sub-types. The antigens may bind to a solid phase. Different antigens are used as a mixture. As far as antigens with multiple epitopes are concerned, they are haptens, i.e. proteins with multiple sequences of a single epitope type. The document U.S. Pat. No. 5,241,047 describes peptides reacting with serums of HIV-positive human guinea pigs. Various epitopes are coupled immediately side by side and may bind by a spacer sequence at the C or N-terminal end to a solid phase. By means of a spacer sequence, spacing of a signal sequence from a carrier material is achieved. One end of the spacer sequence binds to the carrier material, and the other end to an end of the signal sequence. To each spacer sequence is coupled one signal sequence only.

TECHNICAL OBJECT OF THE INVENTION

[0012] The invention is based on the object to specify an immobilizable protein, which can be used for a rapid test of the presence of antibodies in a patient's sample and reliably permits in such a rapid test a detection of many to all groups and sub-types of a causative agent or of antibodies thereagainst.

PRINCIPLES OF THE INVENTION

[0013] As a solution for this technical object, the invention teaches a protein having multiple antigen/epitope sequences for antibodies, the protein being immobilized at a solid phase by at least one binding site, and the antigen/epitope sequences being spaced by bridge compositions in such a way that after binding of the binding site at the solid phase the antigen/epitope sequences are exposed for a binding of the assigned antibodies from the liquid phase.

[0014] The invention is based on a combination of findings. A first finding is that the disadvantages of the application of a mixture of antigens can be avoided by that the antigen/epitopes are combined in a single protein. Then an immobilization can easily take place, without different affinities to the solid phase and/or interactions of different antigens between each other leading to disturbing displacements of the distributions. Then the invention is based on the further finding that it will not be sufficient to just line-up different epitopes and to then bind the product at one end (or both ends) to the solid phase. Rather, it has to be achieved that the epitopes are exposed in a desired manner after the immobilization, i.e. form a secondary and maybe a tertiary structure securing a binding of the assigned antibodies and further permitting a sterical accessibility. Finally, it has been found that this can be achieved by establishing bridge compositions between the epitopes causing on one hand the binding to the solid phase and providing on the other hand the desired exposure. The concept is thus basically the generation of a single protein with several spaced epitopes in turn being separated by interposition of bridge compositions. Further, by adequate selection of the bridge compositions, in particular the structures of the parts of the respective bridge compositions extending on either side of an epitope up to the both-sides binding sites at the solid phase, the epitopes can be folded in a defined way, such that the exposure is reliably secured and also fixed. Finally, it is inherent to the concept of the invention that disturbing interactions of different epitopes of a protein are virtually excluded.

[0015] Suitable bridge compositions can easily be calculated, based on the epitope structures or sequences flanking such connections, by using the principles of molecular modeling. Additionally or alternatively, the average man skilled in the art can experimentally test various bridge compositions for suitability, by that the binding capability of antibodies to the epitopes flanking the bridge compositions are tested by conventional methods.

[0016] It is understood that a protein according to the invention must have ends. One end may be the end of an epitope being neither directly nor indirectly bound to the solid phase. One end may further be an end of a bridge composition, the end of the bridge composition being the binding site or, referred to the connected epitope, may be placed beyond the binding site. One end may finally also be formed by a tag, in particular an affinity tag.

[0017] In principle, there are various possibilities to create a protein according to the invention. For instance, a bridge composition may be formed by insertion of bridge sequences between two antigen/epitope sequences and/or deletion of a partial sequence between two antigen/epitope sequences arranged in a total sequence. The bridge composition may also be formed by fusion of a bridge sequence with two antigen/epitope sequences.

[0018] Bridge compositions may be various molecules. Basically, any organic substances, typically chain type connections, may be used. Examples are oligomers on the basis of identical or different monomers of the polymeric chemistry. It is preferred to form the bridge composition by amino acids. The bridge composition must comprise a binding site for the solid phase. Usually, a positively charged binding site for the binding to a negatively charged solid phase, preferably a membrane, is provided.

[0019] Basically, the antigen/epitope sequences may be identical within a protein. It is particularly preferred, however, if the antigen/epitope sequences bind different antibodies. In an ideal manner, such different antigen/epitope sequences in a protein according to the invention or in a few proteins according to the invention are combined with each other, so that antibodies of the most usual (better all) sub-types of a species of causative agents are detected. The antigen/epitope sequences may for instance be repetitive sequence elements of identical or different HIV sub-types. It is preferred, however, if the antigen/epitope sequences are sequences of different HIV genes and/or strains and/or sub-types.

[0020] In principle, the bridge composition may be formed of any sequence, the bridge composition being for instance a sequence element of gp120. It is preferred if partial sequences unspecifically binding to antibodies contained in blood are deleted. This applies with regard to the bridge composition as well as to the antigen/epitope sequences.

[0021] The invention further relates to the application of proteins according to the invention for producing an immobilizate for the detection of antibodies, wherein first the protein is produced in a dissolved manner, then the protein being bound by at least one binding site to a solid phase, and as an option the solid phase with the protein bound thereto being subjected to at least one rinsing step and/or blocking step, and to the application of a protein according to the invention for performing a HIV test, an immobilizate according to the invention being produced and said immobilizate being placed in a housing, and a detector solution being brought-in in a reaction zone of the immobilizate or being separately added for application to the immobilizate.

[0022] The invention further relates to a polynucleotide, in particular cDNA, coding for a protein according to the invention, an expression vector, preferably plasmide, containing a polynucleotide sequence coding for a protein according to the invention, and a cell being transformed by means of an expression vector according to the invention.

[0023] Finally, the invention relates to a method for the production of a protein according to the invention, the antigen/epitope sequences and the bridge sequences being selected and the order of the lining-up being defined, wherein DNA coding for the antigen/epitope sequences and the bridge sequences is subsequently inserted into an expression vector in the defined manner and under application of a suitable promoter, a cell, preferably E. coli, being transformed by means of the expression vector and transformed cells being selected and cultivated, and wherein the protein expressed from the selected cells is isolated.

[0024] A HIV test according to the invention basically has the following structure. In a “flow through” version, a porous material, in most cases a membrane, is in a device, for instance a plastic housing having an access opening to the membrane. At surfaces of the membrane being accessible to liquids, at least one protein type according to the invention is immobilized. Through the access opening, a sample to be tested, for instance blood, serum or plasma, is applied on the membrane. Among other reasons, because of the capillary forces the sample will enter into the membrane or will pass through it. This can further be supported, for instance, by placing an absorbent material under the membrane. The sample or antibodies contained therein, respectively, react with the protein. By applying a conventional detector solution, for instance colored particles such as colloidal gold particles, a visual proof for the binding of antibodies to the protein is achieved. Alternatively to the “flow through” technology, a “lateral flow” method can be used. Therein a membrane is used, too, being however separated in a lateral direction into an application zone and a reaction zone. Caused by the capillary effect, the sample applied in the application zone will pass into the reaction zone where at least one protein type according to the invention is immobilized. In the application zone, there will be no proteins according to the invention immobilized, it is however possible to immobilize other substances, e.g. proteins, not binding the antibodies to be detected, however binding substances not desired in the sample and thus separating them. Thereby the reliability of the antibody detection is substantially improved, since undesired interactions because of other blood components can be excluded. The reaction zone may already contain a detector substance, however it may also possible that in the detector zone separately an application of detector solution is made.

[0025] The production of a total sequence of antigen/epitope sequences and interposed bridge compositions being charged, for instance positively charged, has further special preparative advantages. If such a protein is produced gene-technologically by expression in a cell, first a purification of the protein from a cell extract is useful. The charges of the bridge compositions permit now a particularly effective and simple purification to very high purity levels in an ion exchange chromatography, since the isoelectrical point is extremely high. By such purification of a protein produced by gene technology according to the invention before the immobilization method step, thus a particularly pure immobilizate with regard to bound protein is obtained. This increases the reliability of a test system to a substantial degree.

[0026] Definitions

[0027] The term HIV test designates a detection method for HIV antibodies in body components, in particular body liquids. Body liquids are for instance blood, serum, plasma, saliva, urine or liquor.

[0028] The term protein comprises, in the framework of the invention, compositions containing natural or non-natural amino acid sequences. A protein may be synthesized or at any case isolated with regard to the amino acid sequences. Insofar the term protein also comprises peptides. A protein needs not necessarily be formed of amino acids only. In particular the bridge composition may be structured differently than of amino acids.

[0029] As an antibody is designated a substance formed by an immune reaction in an organism in a natural manner after an infection, such substance being capable to specifically bind to the causative agent of the infection or components thereof.

[0030] As an antigen is designated a substance being capable to specifically bind to an antibody. Antigens and antibodies are assigned to each other on the basis of the antibody or antibodies to be detected.

[0031] An antigen/epitope sequence is an amino acid sequence, formed of natural and/or non-natural amino acids on one hand being chemically bindable to an assigned antibody, and on the other hand having such a secondary and/or tertiary structure that the purely chemical binding is also possible in a sterical manner, i.e. to the “key/lock principle”.

[0032] The term immobilization designates the binding of a substance from the liquid phase to a solid phase surface. The term binding comprises the chemisorption, the ionic binding, the covalent binding and intermediate types of such bindings.

[0033] A bridge composition typically is an oligomer composition, with the kind of monomers, the order or sequence and the spatial orientation thereof including any internal or external linkage being defined. In particular are defined the positions of the ends of the bridge composition with respect to each other. It might happen that the antigen/epitope sequence respectively connected or to be connected and the opposing bridge composition are to be considered, if the number of the degrees of freedom of the bridge composition does not easily permit a sufficiently clear definition of the spatial position of the ends. A bridge composition is not necessarily an artificial sequence or a sequence artificially inserted between two antigen/epitope sequences. It may also be a native sequence between two naturally spaced antigen/epitope sequences, wherein one or more amino acids may also be exchanged.

[0034] A binding site is, in the terminology of the patent claims, a reactive group of the bridge composition, by means of which an immobilization at the solid phase can be achieved.

[0035] Exposure of an antigen/epitope sequence is the setting of the secondary and/or tertiary structure of the sequence such that a binding to the destination antibody can be performed. In particular this means the folding in the area of the antigen/epitope sequence. Folding may also take place with the integration of generating disulfide bridges. The folding will usually lead to the generation of a specific loop. An incorrect folding will lead to an incorrect loop. An incorrect folding may take place, if the ends of an antigen/epitope sequence are stabilized relative to each other in a not suitable manner.

[0036] With the feature of the bridge composition it is basically achieved that the parts of two bridge compositions being arranged between two adjacent binding sites will stabilize the ends of the interposed antigen/epitope sequence such that the desired folding is obtained. It is essential, herein, that the two binding sites are geometrical fixed points, due to the binding to the solid phase. Of course, non-functional sequences may be interposed between the end of a bridge composition and the antigen/epitope sequence connected thereto, as long as this will not affect the conditions described above.

[0037] A bridge sequence is a bridge composition being formed of multiple natural and/or non-natural amino acids.

[0038] The term of the different antibodies means antibodies of different type or of different structure. Corresponding considerations apply to genes, strains, sub-types and the like.

[0039] The term specificity designates the capability of a substance to detect out of a number of interaction possibilities or reaction possibilities provided a certain one or a group of certain ones. An antigen being specific for a certain antibody or a certain binding site of an antibody will have no reaction with other antibodies not having this binding site and being present in a sample, possibly after separation of the substances disturbing this binding site. In contrast thereto, antigens or sequences binding a multitude of different antibodies in a sample are not specific.

[0040] The term detection designates the generation of an arbitrary detector signal, observable directly by means of the human senses or indirectly by means of physical/chemical measuring methods, said detector signal having its cause in an antibody/antigen binding event. In the simplest case, it is a color reaction. Detection methods for antibody/antigen binding events are known in various ways to the man skilled in the art and need not be explained here in more detail.

[0041] A detector solution comprises one or more substances being capable to generate a detector signal upon an antibody/antigen binding event.

[0042] The term solid phase designates a solid body with a surface capable to bind binding sites.

[0043] A rinsing step comprises rinsing of a generated immobilizate, i.e. a solid phase with a protein bound thereto, with a solution removing weakly bound proteins and/or other substances from the surface of the solid phase.

[0044] A blocking step comprises rinsing of an immobilizate with a solution comprising one or more substances, saturating those zones of the surface of the solid phase not gone in binding condition with the protein, i.e. blocking them for the binding of other substances directly at the surface of the solid phase.

EMBODIMENTS OF THE INVENTION

[0045] In the following, not limiting examples only of embodiments of the invention are described in more detail.

[0046] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0047] In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.

EXAMPLE 1

[0048] In the following, examples for artificial bridge compositions are given which can be used for a protein according to the invention for the detection of HIV antibodies.

[0049] The bridge composition 1 may comprise the following sequence:

[0050] GKR--K-RK-KR--RRG

[0051] with “-” representing one or more of any amino acids. An example for such a bridge composition is:

[0052] GKRAHKSRKHNYKRHIRRG

[0053] The bridge composition 2 may comprise the following sequence:

[0054] G-KK-RR-KGK-RR-KK-G

[0055] with “-” representing one or more of any amino acids. An example for such a bridge composition is:

[0056] GSKKARRIKGKIRRLKKVG

[0057] The bridge composition 3 may comprise the following sequence:

[0058] G-C-K-R-KRKXKRK-K-C-G

[0059] with “-” representing one or more of any amino acids, and “X” representing D or E. An example for such a bridge composition is:

[0060] GVCIKHRYKRKDKRKHKVACIG

[0061] The letters in the sequence information above and below are based on the single letter code.

EXAMPLE 2

[0062] In the following, a native bridge composition is stated which is suitable for a protein according to the invention for the detection of HIV antibodies.

[0063] GVA-K-KRR---REKRAVG

[0064] with “-” representing an arbitrary amino acid. This bridge composition comes from the HVI-1 envelope gene.

EXAMPLE 3

[0065] In the following, proteins according to the invention under application of bridge compositions, e.g. from examples 1 and/or 2, are described in more detail. Table 1 supplies possibilities of the deletion and/or insertion of bridge compositions in sequences with antigen/epitopes. Suitable sequences ID I to ID VI with antigen/epitopes are shown in FIGS. 1a-f, these being complete sequences of HIV proteins (for the purpose of the present invention, it is however not necessary to use complete sequences).

[0066] Table 1 is to be read in such a way that in the leftmost and the leftmost but one column a starting protein, ID I to ID VI, being suitable for the generation of a protein according to the invention is shown. The further columns indicate whether and where deletions and/or insertions with bridge compositions, for instance according to table 2, can be inserted into the starting protein in order to obtain a protein according to the invention. In table 2 are: ID 2 to 3 artificial bridge compositions, ID 4 a natural bridge composition (from the transition gp120/gp41 in env), ID 5 to 8 HIV-10-sequences, ID 9 to 12 Gnann region from HIV-2 and ID 13 to 36 V3 loop sequences from HIV-1 (consensus sequences of the respective sub-types and sequences similar thereto, also from sub-type 0).

[0067] A protein according to the invention can for instance be obtained, if in pol 2 having 289 amino acids at position 31 either the bridge composition 1 or the bridge composition 2 from table 2 are inserted, not however bridge composition 3. As a result, the unlimited combination possibilities stated in table 1 are obtained.

[0068] From the graphic overviews of FIGS. 1a-f, deletions and possible insertion positions of table 2 can also be taken. In the sequences, the symbol “+1/2/3+” corresponds to the insertion of the bridge composition 1, 2 or 3. “+1/2+” also stands for an insertion of one of the bridge compositions 1 or 2.

EXAMPLE 4

[0069] In FIG. 2 are shown the sequences Seq. ID A to E, with A to D being proteins according to the invention, E however a protein not according to the invention. In the sequences A to D modifications are performed such that between the antigen/epitope sequences suitable bridge compositions will be formed. In contrast thereto, in E will not take place a sufficient presentation of antigen/epitope sequences. In FIGS. 3a/b, the structures of the proteins C to E are shown, and reference is made to the following examples.

EXAMPLE 5

[0070] In this example, the production of a protein according to the invention is described, namely of p31 Δ100/40, 140/23, 163/14 Ω31/2, 100/3

[0071] with the meaning:

[0072] ΔX/Y (e.g. Δ100/76): behind the amino acid at position 100, 76 amino acids are deleted, and

[0073] ΩX/Y (e.g. Ω30/2): behind the amino acid at position 30, bridge composition 2 is inserted.

[0074] Partial Step 1

[0075] The fragment 1 is obtained by the PCR technology. As primers for the amplification are used the oligonucleotides 5′-ATATGGCATATGTTTTTAGATGGAATAGATAAGGCCC-3′ and 5′-TATAGGGCCCAGGTGGCAGGTTAAAA-3′

[0076] as a template the HIV-pol gene is used. The PCR reaction is performed to a conventional protocol. The desired PCR product (approx. 110 bp) is isolated and subjected to a restriction with ApaI and NdeI.

[0077] Fragment 1 (Epitope 1, PCR)         NdeI atatggCATATGTTTTTAGATGGAATAGATAAGGCCC     ........TTTTTAGATGGATAGATAAGGCCCGATGAACATGAGAAATATCACAGTAATTGGAGA           M  F  L  D  G  I  D  K  A  Q  D  E  H  E  K  Y  H  S  N  W  R     ........AAAAATCTACCTTATCTATTCCGGGTTCTACTTGTACTCTTTATAGTGTCATTAACCTCT             GCAATGGCTAGTGATTTTAACCTGCCACCT.......................              A  M  A  S  D  F  N  L  P  P             CGTTACCGATCACTAAAATTGGACGGTGGA                           AAAATTGGACGGTGGACCCGGGatat                                            ApaI

[0078] Partial Step 2

[0079] Two oligonucleotides 5′-CAAAAAGGCCCGTCGCATCAAGGGCAAAATGCGACGGGTGAAGAAA G-3′ and 5′-CCGGCTTTCTTCACCCGTCGCATTTTGCCCTTGATGCGACGGGCCTT TTTGGGCC-3′

[0080] are denaturated for a short time at 100° C., hybridized with each other at a linearly dropping temperature gradient, and the double-strand product is then isolated.

[0081] Fragment 2 (Bridge Composition 2, Synthetic) ApaI     CAAAAAGGCCCGTCGCATCAAGGGCAAAATGCGACGGGTGAAGAAAG G  P  K  K  A  R  R  I  K  G  K  M  R  R  V  K  K  A  G CCGGGTTTTTCCGGGCAGCGTAGTTCCCGTTTTACGCTGCCCACTTCTTTCGGCC NgoMIV

[0082] Partial Step 3

[0083] The fragment 3 is obtained by PCR technology. As primers for the amplification are used the oligonucleotides 5′-TAATTTGCCGGCGTAGTAGCAAAAGAAATAGTAG-3′ and 5′-TATAGCATGCTCCATATGCTGTTTCCTGCCCTGT-3′

[0084] as a template the HIV-pol gene is used. The PCR reaction is performed to a conventional protocol. The desired PCR product (233 bp) is subjected to a restriction with NgoMIV and SphI and is then isolated.

[0085] Fragment 3 (Epitope 2, PCR) (233 bp)       NgoMIV taatttGCCGGCGTAGTAGCAAAAGAAATAGTAG             GTAGTAGCAAAGAAATAGTAGCCAGCTGTGATAAATGTCAGCTAAAAGGAGAAGCCATG       A   G  V  V  A  K  E  I  V  A  S  C  D  K  C  Q  L  K  G  E  A  M             CATGGACAAGTAGACTGTAGTCCAGGAATATGGCAACTAGATTGTACACATTTAGAAGGA              H  C  Q  V  D  C  S  P  G  I  W  Q  L  D  C  T  H  L  E  G             AAAGTTATCCTGGTAGCAGTTCATGTAGCCAGTGGATATATAGAAGCAGAAGTTATTCCA              K  V  I  L  V  A  V  H  V  A  S  G  Y  I  E  A  E  V  I  P             GCAGAAACAGGGCAGGAAACAGCATAT              A  E  T  G  Q  E  T  A  Y  C  A  C             CGTCTTTGTCCCCTCCTTTGTCCTATA                   TGTCCCGTCCTTTGTCGTATACCTCGTACGatat                                            SphI

[0086] Partial Step 4

[0087] Two oligonucleotides 5′-CATGCATCAAACACCGCTACAAGCGACGCGATCGTCGGAAGCATAAA GTGGCCTGC-3′ and 5′-CTAGGCAGGCCACTTTATGCTTCCGACGATCGCGTCGCTTGTAG CGGTGTTTGATG-3′

[0088] are denaturated for a short time at 100° C., hybridized with each other at a linearly dropping temperature gradient, and the double-strand product is then isolated.

[0089] Fragment 4 (Bridge Composition 3, Synthetic) SphI CATGCATCAAACACCGCTACAAGCGACGCGATCGTCGGAAGCATAAAGTGGCCTGC A  C  I  K  H  R  Y  K  R  R  D  R  R  K  H  K  V  A  C  I  G     GTAGTTTGTGGCGATGTTCGCTGCGCTAGCAGCCTTCGTATTTCACCGGACGGATC AvrII 

[0090] Partial Step 5

[0091] The fragment 5 is obtained by PCR technology. As primers for the amplification are used the oligonucleotides 5′-ATTATCCTAGGTCAAATGGCAGTATTCATCCAC-3′ and 5′-TATAGGATCCTAATCCTCATCCTGTCTACTTGC-3′

[0092] as a template the HIV-pol gene is used. The PCR reaction is performed to a conventional protocol. The desired PCR product (360 bp) is subjected to a restriction with AvrII and BamHI and is then isolated.

[0093] Fragment 5 (Epitope 3, PCR)       AvrII attatCCTAGGTCAAATGGCAGTATTCATCCAC             CAAATGGCAGTATTCATCCACAATTTTAAAAGAAAAGGGGGGATTGGGGGGTACAGTGCA         C  I  G  Q  M  A  V  F  I  H  N  F  K  R  K  G  G  I  G  G  Y  S  A             GGGGAAAGAATAGTAGACATAATAGCAACAGACATACAAACTAAAGAATTACAAAAACAA              G  E  R  I  V  D  I  I  A  T  D  I  Q  T  K  E  L  Q  K  Q             ATTACAAAATTCAAAATTTTCGGGTTTATTACAGGGACAGCAGAAATCCACTTTGGAAA              I  T  K  I  Q  N  F  R  V  Y  Y  R  D  S  R  N  P  L  W  K             GGACCAGCAAAAAGCTCCTCTGGAAAGGTGAAGGGGCAGTAGTAAATACAAGATAATAGTGAC              G  P  A  K  L  L  W  K  G  E  G  A  V  V  I  Q  D  N  S  D             ATAAAAGTAGTGCCAAGAAGAAAAGCAAAGATCATTAGGGATTATGGAAAACAGATGGCA              I  K  V  V  P  R  R  K  A  K  I  I  R  D  Y  G  K  Q  M  A             GGTGATGATTGTCTGGCAAGTAGACAGGATGAGGATTAG              G  D  D  C  V  A  S  R  Q  D  E  D  *             CCACTACTAACACACCGTTCATCTGTCCTACTCCTAATC                            CGTTCATCTGTCCTACTCCTAATCCTAGGatat                                                    BamHI

[0094] Partial Step 6

[0095] A suitable expression vector is cut with NdeI and BamHI, and the vector fragment is isolated.

[0096] Partial Step 7

[0097] The purified vector fragment and the respectively isolated partial fragments are linked to each other by means of ligation reactions.

[0098] Partial Step 8

[0099] Suitable E. coli cells are transformed and selected with the ligation products.

[0100] Partial Step 9

[0101] From obtained colonies is isolated the plasmide DNA and tested for the presence, arrangement and orientation of the partial sequences with the enzymes NdeI, ApaI, NgoMIV, SphI, AvrII and BamHI in different combinations. Plasmide DNA with a positive result is sequenced for confirmation.

[0102] P31 native

[0103] P31Δ100/40, 140/23, 163/14 Ω31/2, 100/3

[0104] Frg.1 Frg.2 Frg.3 Frg.4 Frg.5

[0105] NdeI ApaI NgoMIV SphI AvrII BamHI

[0106] Total nucleotide sequence: CATATGTTTTTAGATGGAATAGATAAGGCCCAAGATGAACATGAGAAATA TCACAGTAATTGGAGAGCAATGGCTAGTGATTTTAACCTGCCACCTGGGC CCAAAAAGGCCCGTCGCATCAAGGGCAAAATGCGACGGGTGAAGAAAGCC GGCGTAGTAGCAAAAGAAATAGTAGCCAGCTGTGATAAATGTCAGCTAAA AGGAGAAGCCATGCATGGACAAGTAGACTGTAGTCCAGGAATATGGCAAC TAGATTGTACACATTTAGAAGGAAAAGTTATCCTGGTAGCAGTTCATGTA GCCAGTGGATATATAGAAGCAGAAGTTATTCCAGCAGAAACAGGGCAGGA AACAGCATATGGAGCATGCATCAAACACCGCTACAAGCGACGCGATCGTC GGAAGCATAAAGTGGCCTGCCTAGGTCAAATGGCAGTATTCATCCACAAT TTTAAAAGAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGT AGACATAATAGCAACAGACATACAAACTAAAGAATTACAAAAACAAATTA CAAAAATTCAAAATTTTCGGGTTTATTACAGGGACAGCAGAAATCCACTT TGGAAAGGACCAGCAAAGCTCCTCTGGAAAGGTGAAGGGGCAGTAGTAAT ACAAGATAATAGTGACATAAAAGTAGTGCCAAGAAGAAAAGCAAAGATCA TTAGGGATTATGGAAAACAGATGGCAGGTGATGATTGTGTGGCAAGTAGA CAGGATGAGGATTAGGATCC

[0107] Total amino acid sequence: MFLDGIDKAQDEHEKYHSNKRAMASDFNLPPGPKKARRIKGKMRRVKKAG VVAKEIVASCDKCQLKGEAMHGQVDCSPGIWQLDCTHLEGKVILVAVHVA SGYIEAEVIRAETGQETAYGACIKHRYKRRDRRKHKVACIGQMAVFIHNF KRKGGIGGYSAGERIVDIIATDIQTKELQKQITHIQNFRVYYRDSRNPLW KGPAKLLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCVASRQ DED*

[0108] The entire disclosures of all applications, patents and publications, cited herein and of corresponding German application No. 101 06 295, filed Feb. 2, 2001 is incorporated by reference herein.

[0109] The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

[0110] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

[0111] The expression of a protein according to the invention is performed as follows. After the coding nucleic acid for the expressing protein having been produced and built-in over restriction interfaces into a commercially available vector, a transformation of the plasmide into a commercially available E. coli cell takes place. After inoculation of a medium (e.g. LB medium) with the transformation addition, the breeding of the cell culture by incubation is performed at an optimum temperature (e.g. 37° C.). The protein expression is induced by addition of isopropyl β-D thiogalactopyranoside (IPTG) and achieved by continuation of the incubation. After harvesting the E. coli cells by centrifugation, a cell lysis with a lysis buffer (for instance a guanidine hydrochloride containing buffer).

[0112] Purification of the protein can be achieved by conventional chromatography methods (for instance ion exchange chromatography and gel chromatography), the isoelectrical point of the proteins increased by the insertion of positively charged sequences being used in an advantageous manner to substantially enrich the proteins by cation exchange chromatography. Usually the chromatographic separations are performed by means of chromatography columns brought into the material. If the proteins have been provided with a “tag” (e.g. a N or C-terminal His6 peptide, a “flag tag” or a myc epitope), they can be purified by utilization of an affinity chromatography, the respective protein being bound by the “tag” to the corresponding affinity chromatography material (e.g. for the His6 tag to Ni-NTA material). After the material having been washed several times with corresponding washing buffers, the desired protein is separated from the material by means of at least one elution buffer (for instance by a buffer with substantially higher or lower pH value). Finally, the eluates are subjected to several dialysis steps, in order to permit further use of the protein.

EXAMPLE 6

[0113] In this example, the production of an immobilizate according to the invention is described. The purified protein is diluted in a suitable manner with an aqueous solution of 100 mM NaCl and 0.4-0.8% SDS. From this solution, 0.5 μl is applied by means of a BioDot device (Cambridge, UK) on a nitrocellulose membrane, so that on a spot of 3-4 mm diameter there are 250 ng protein. After application of the protein, the membrane is dried for at least one hour, before the detection reaction is performed.

[0114] An immobilizate is obtained, wherein the arrangement and the folding of the protein is achieved in a way that is diagrammatically shown in FIG. 3a. The epitopes are separated by a positively charged peptide sequence, permitting an adhesion to, the membrane and a correct folding of the epitopes (underlined sequence sections).

[0115] It may be noted, with regard to the folding shown in FIG. 3a, that possibly not all protein molecules applied on the solid phase can be folded in the sketched way. Part of the molecules may, caused by the lysis of the cells and the subsequent purification procedure, be present in a disordered (denaturated) folding condition. For the purpose of the present invention it is however sufficient, if for a protein structured according to the invention the probability of a folding suitable for the binding of antibodies, induced by the optimum adhesion on the solid phase permitted by the integration of the bridge compositions, is clearly increased in comparison to a protein containing no bridge compositions. By this increased probability of the “correct” folding, the possibility of the binding of antibodies is in total substantially improved, and thus the increase in sensitivity of the whole detection method is secured.

EXAMPLE 7

[0116] To an immobilizate from example 6 have been fed serums of various HIV positive patients, and the reaction was examined by means of a detector solution. In all cases a color reaction specific for the binding antibody/antigen was observed. Incorrect negative results were not obtained. Tests with serums of HIV negative patients showed that not a single incorrect positive result was obtained.

EXAMPLE 8

[0117] In this comparison example, an immobilizate has been produced with a protein env 4 (ID E) according to the procedure of example 6. The difference is however, as can be seen from a comparison of FIGS. 3a and 3 c, that between the epitopes arranged at the left side there is no positively charged bridge composition. It can further be seen that thereby the two epitopes on the left side are closely arranged to each other and are folded—under formation of disulfide bridges destroying the antigenicity—such that binding of an antibody cannot be achieved.

[0118] With the same protein amount as in example 7, again tests with serums of various HIV positive patients have been made. Without exception, no reaction was shown, that is regularly incorrect negative results were obtained.

EXAMPLE 9

[0119] In this example a protein (ID D) according to the invention or an immobilizate with repetitive sequence elements of different sub-types (identical ones are also possible) is diagrammatically represented with reference to FIG. 3b. This protein according to the invention is formed of V3 loops only of different HIV sub-types being separated by a positively charged sequence element of gp120.

EXAMPLE 10

[0120] A rapid test according to the invention is configured as follows. An immobilizate according to example 6 is positioned and fixed in a plastic housing underneath an access opening such that at least part of the immobilizate is open for access. The immobilizate is placed on an absorbing material, for instance cotton wool. A separately packed detector solution belongs to the rapid test.

[0121] The detection of antibodies bound to the antigen may be performed by means of a detection solution containing a conjugate of protein A with colloidal gold. The application of such conjugates in immunological test methods is generally known in the art and has been described in the literature. This conjugate may for instance be produced, as described in U.S. Pat. No. 5,541,059, by mixing 100 ml of a colloidal gold solution (commercially available) with 100 ml of 0.006 mg/ml protein A solution (protein A is commercially available in a lyophilized form and as a solution). Alternatively a protein A-gold conjugate may commercially be acquired.

[0122] The binding of the conjugate to the bound antibodies can visually be detected. In this example, a red stain will appear if bound antibodies are present.

[0123] Alternatively to the conjugates with colloidal gold a dye suspension can be used, with protein A being adsorbed to a water-insoluble dye.

[0124] A rapid test is performed as follows. A human guinea pig is lightly injured by a prick. The resulting drop of blood is received in a small capillary. The capillary with the blood is then given into a container together with a suitable solvent, for instance physiological sodium chloride solution, and is agitated until blood and solvent are fully mixed. The contents of the container is then fed through the access opening on the immobilizate. Then, the detector solution is added, and it is visually monitored whether a coloration of the immobilizate visible through the access opening takes place. Coloration means that HIV antibodies exist in the blood of the human guinea pig. If there is no coloration, the result is negative.

1 97 1 17 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 1 Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg 1 5 10 15 Gly 2 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 2 Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys 1 5 10 15 Lys Xaa Gly 3 22 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 3 Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Lys Xaa Lys Arg Lys Xaa 1 5 10 15 Lys Xaa Xaa Cys Xaa Gly 20 4 20 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 4 Gly Val Ala Xaa Xaa Lys Xaa Lys Arg Arg Xaa Xaa Xaa Arg Glu Lys 1 5 10 15 Arg Ala Val Gly 20 5 22 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 5 Trp Ile Gln Leu Gln Gln Arg Leu Asn Leu Trp Gly Cys Arg Gly Lys 1 5 10 15 Leu Ile Cys Tyr Thr Asn 20 6 22 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 6 Trp Ile Gln Asn Gln Gln Leu Leu Asn Leu Trp Gly Cys Lys Gly Arg 1 5 10 15 Leu Val Cys Tyr Thr Asn 20 7 22 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 7 Trp Leu Gln Asn Gln Gln Ile Leu Asn Leu Trp Gly Cys Lys Gly Arg 1 5 10 15 Leu Ile Cys Tyr Thr Asn 20 8 22 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 8 Trp Leu Gln Ser Gln Gln Leu Leu Ser Asn Trp Gly Cys Arg Gly Lys 1 5 10 15 Leu Val Cys Tyr Thr Asn 20 9 24 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 9 Ala Ile Glu Arg Tyr Leu Gln Asp Gln Ala Arg Leu Asn Ser Trp Gly 1 5 10 15 Cys Thr Phe Arg Gln Val Cys His 20 10 24 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 10 Ala Met Glu Lys Tyr Leu Arg Asp Gln Ala Ile Val Asn Ser Trp Gly 1 5 10 15 Cys Ala Phe Arg Gln Val Cys Tyr 20 11 24 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 11 Ala Met Glu Lys Tyr Leu Lys Asp Gln Ala Arg Leu Asn Ser Trp Gly 1 5 10 15 Cys Ala Phe Arg Gln Val Cys His 20 12 24 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 12 Ala Ile Glu Lys Tyr Leu Lys His Gln Ala Gln Leu Asn Ala Trp Gly 1 5 10 15 Cys Ala Phe Arg Gln Val Cys His 20 13 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 13 Thr Arg Lys Ser Ile His Ile Gly Pro Gly Gln Ala Phe Tyr Ala Thr 1 5 10 15 Gly Asp 14 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 14 Thr Arg Arg Ser Ile Ser Phe Gly Ile Gly Pro Gly Gln Ala Leu Tyr 1 5 10 15 Thr Thr 15 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 15 Thr Arg Gln Arg Thr Pro Ile Gly Leu Gly Gln Ala Leu Tyr Thr Thr 1 5 10 15 Gly Gln Phe 16 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 16 Arg Thr Val Gln Glu Ile Arg Ile Gly Pro Met Ala Trp Tyr Ser Met 1 5 10 15 Gly Ala 17 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 17 Thr Met Lys Arg Thr Ser Ile His Ile Gly Pro Gly Gln Thr Phe Tyr 1 5 10 15 Ala Thr 18 17 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 18 Thr Arg Arg Gly Ile Pro Leu Gly Pro Gly Arg Ala Trp Tyr Ala Thr 1 5 10 15 Leu 19 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 19 Asp Ser Thr Arg Glu Ser Met Arg Ile Gly Pro Gly Gln Ala Phe Tyr 1 5 10 15 Ala Thr Gly 20 17 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 20 Ile Arg Gln Gly Ile His Ile Gly Pro Gly Arg Ala Phe Phe Ala Ala 1 5 10 15 Trp 21 16 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 21 Asp Val Gln Glu Met Arg Ile Gly Pro Met Ala Trp Tyr Ser Met Gly 1 5 10 15 22 20 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 22 Ile Cys Thr Arg Arg Gly Ile Arg Met Gly Pro Gly Gln Val Val Tyr 1 5 10 15 Ala Thr Cys Thr 20 23 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 23 Thr Ile Val Gln Ile Lys Ile Ile Gly Pro Leu Ala Val Tyr Ser Met 1 5 10 15 Tyr Gly 24 16 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 24 Thr Arg Lys Ser Val Arg Ile Gly Pro Gly Gln Ala Phe Tyr Ala Thr 1 5 10 15 25 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 25 Gly His Thr Arg Lys Ser Ile Arg Ile Gly Pro Gly Gln Thr Phe Tyr 1 5 10 15 Ala Thr 26 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 26 Asn Thr Arg Gln Ser Thr His Ile Gly Pro Gly Ala Leu Tyr Thr Thr 1 5 10 15 Lys Ile Glu 27 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 27 Thr Arg Lys Ser Ile His Leu Gly Pro Gly Gln Ala Phe Tyr Ala Thr 1 5 10 15 Gly Asp 28 20 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 28 Tyr Gln Thr Arg Lys Ser Ile Arg Ile Gly Pro Gly Gln Ala Phe Tyr 1 5 10 15 Ala Thr Gly Asp 20 29 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 29 Thr Val Gln Glu Ile Arg Ile Gly Pro Met Ala Trp Tyr Ser Met Gly 1 5 10 15 Asn Val 30 16 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 30 Thr Arg Ile Ser His Thr Ile Gly Pro Gly Arg Val Phe Tyr Arg Thr 1 5 10 15 31 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 31 Thr Arg Lys Gly Ile His Met Gly Pro Gly Gln Val Leu Tyr Ala Thr 1 5 10 15 Lys Pro 32 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 32 His Thr Arg Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala 1 5 10 15 Thr Ser 33 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 33 Thr Arg Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Thr Thr 1 5 10 15 Ser Met Gln 34 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 34 Gln Thr Arg Thr Ser Ile Thr Ile Gly Pro Gly Gln Val Phe Tyr Arg 1 5 10 15 Thr Glu 35 18 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 35 Gly Thr Arg Lys Ser Val Arg Ile Gly Pro Gly Gln Thr Phe Tyr Ala 1 5 10 15 Thr Gly 36 17 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 36 Thr Arg Lys Gly Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr 1 5 10 15 Gly 37 14 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 37 Ala Val Gly Ile Gly Ile Asn Cys Thr Arg Pro Asn Asn Asn 1 5 10 38 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 38 Gly Asp Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Ile Gly Pro 1 5 10 15 Thr Pro Thr 39 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 39 Gly Lys Arg Ala His Lys Ser Arg Lys His Asn Tyr Lys Arg His Ile 1 5 10 15 Arg Arg Gly 40 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 40 Gly Ser Lys Lys Ala Arg Arg Ile Lys Gly Lys Met Arg Arg Leu Lys 1 5 10 15 Lys Val Gly 41 22 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 41 Gly Val Cys Ile Lys His Arg Tyr Lys Arg Lys Asp Lys Arg Lys His 1 5 10 15 Lys Val Ala Cys Ile Gly 20 42 37 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 42 atatggcata tgtttttaga tggaatagat aaggccc 37 43 26 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 43 tatagggccc aggtggcagg ttaaaa 26 44 37 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 44 atatggcata tgtttttaga tggaatagat aaggccc 37 45 60 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 45 tttttagatg gaatagataa ggcccaagat gaacatgaga aatatcacag taattggaga 60 46 21 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 46 Met Phe Leu Asp Gly Ile Asp Lys Ala Gln Asp Glu His Glu Lys Tyr 1 5 10 15 His Ser Asn Trp Arg 20 47 30 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 47 gca atg gct agt gat ttt aac ctg cca cct 30 Ala Met Ala Ser Asp Phe Asn Leu Pro Pro 1 5 10 48 10 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 48 Ala Met Ala Ser Asp Phe Asn Leu Pro Pro 1 5 10 49 26 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 49 tatagggccc aggtggcagg ttaaaa 26 50 47 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 50 caaaaaggcc cgtcgcatca agggcaaaat gcgacgggtg aagaaag 47 51 55 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 51 ccggctttct tcacccgtcg cattttgccc ttgatgcgac gggccttttt gggcc 55 52 47 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 52 caaaaaggcc cgtcgcatca agggcaaaat gcgacgggtg aagaaag 47 53 19 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 53 Gly Pro Lys Lys Ala Arg Arg Ile Lys Gly Lys Met Arg Arg Val Lys 1 5 10 15 Lys Ala Gly 54 55 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 54 ccggctttct tcacccgtcg cattttgccc ttgatgcgac gggccttttt gggcc 55 55 34 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 55 taatttgccg gcgtagtagc aaaagaaata gtag 34 56 34 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 56 tatagcatgc tccatatgct gtttcctgcc ctgt 34 57 34 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 57 taatttgccg gcgtagtagc aaaagaaata gtag 34 58 60 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 58 gtagtagcaa aagaaatagt agccagctgt gataaatgtc agctaaaagg agaagccatg 60 59 22 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 59 Ala Gly Val Val Ala Lys Glu Ile Val Ala Ser Cys Asp Lys Cys Gln 1 5 10 15 Leu Lys Gly Glu Ala Met 20 60 60 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 60 cat gga caa gta gac tgt agt cca gga ata tgg caa cta gat tgt aca 48 His Gly Gln Val Asp Cys Ser Pro Gly Ile Trp Gln Leu Asp Cys Thr 1 5 10 15 cat tta gaa gga 60 His Leu Glu Gly 20 61 20 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 61 His Gly Gln Val Asp Cys Ser Pro Gly Ile Trp Gln Leu Asp Cys Thr 1 5 10 15 His Leu Glu Gly 20 62 60 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 62 aaa gtt atc ctg gta gca gtt cat gta gcc agt gga tat ata gaa gca 48 Lys Val Ile Leu Val Ala Val His Val Ala Ser Gly Tyr Ile Glu Ala 1 5 10 15 gaa gtt att cca 60 Glu Val Ile Pro 20 63 20 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 63 Lys Val Ile Leu Val Ala Val His Val Ala Ser Gly Tyr Ile Glu Ala 1 5 10 15 Glu Val Ile Pro 20 64 27 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonuccleotide 64 gcagaaacag ggcaggaaac agcatat 27 65 12 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 65 Ala Glu Thr Gly Gln Glu Thr Ala Tyr Gly Ala Cys 1 5 10 66 34 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 66 tatagcatgc tccatatgct gtttcctgcc ctgt 34 67 56 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 67 catgcatcaa acaccgctac aagcgacgcg atcgtcggaa gcataaagtg gcctgc 56 68 56 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 68 ctaggcaggc cactttatgc ttccgacgat cgcgtcgctt gtagcggtgt ttgatg 56 69 56 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 69 catgcatcaa acaccgctac aagcgacgcg atcgtcggaa gcataaagtg gcctgc 56 70 21 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 70 Ala Cys Ile Lys His Arg Tyr Lys Arg Arg Asp Arg Arg Lys His Lys 1 5 10 15 Val Ala Cys Ile Gly 20 71 56 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 71 ctaggcaggc cactttatgc ttccgacgat cgcgtcgctt gtagcggtgt ttgatg 56 72 33 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 72 attatcctag gtcaaatggc agtattcatc cac 33 73 33 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 73 tataggatcc taatcctcat cctgtctact tgc 33 74 33 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 74 attatcctag gtcaaatggc agtattcatc cac 33 75 339 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 75 caaatggcag tattcatcca caattttaaa agaaaagggg ggattggggg gtacagtgca 60 ggggaaagaa tagtagacat aatagcaaca gacatacaaa ctaaagaatt acaaaaacaa 120 attacaaaaa ttcaaaattt tcgggtttat tacagggaca gcagaaatcc actttggaaa 180 ggaccagcaa agctcctctg gaaaggtgaa ggggcagtag taatacaaga taatagtgac 240 ataaaagtag tgccaagaag aaaagcaaag atcattaggg attatggaaa acagatggca 300 ggtgatgatt gtgtggcaag tagacaggat gaggattag 339 76 115 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 76 Cys Ile Gly Gln Met Ala Val Phe Ile His Asn Phe Lys Arg Lys Gly 1 5 10 15 Gly Ile Gly Gly Tyr Ser Ala Gly Glu Arg Ile Val Asp Ile Ile Ala 20 25 30 Thr Asp Ile Gln Thr Lys Glu Leu Gln Lys Gln Ile Thr Lys Ile Gln 35 40 45 Asn Phe Arg Val Tyr Tyr Arg Asp Ser Arg Asn Pro Leu Trp Lys Gly 50 55 60 Pro Ala Lys Leu Leu Trp Lys Gly Glu Gly Ala Val Val Ile Gln Asp 65 70 75 80 Asn Ser Asp Ile Lys Val Val Pro Arg Arg Lys Ala Lys Ile Ile Arg 85 90 95 Asp Tyr Gly Lys Gln Met Ala Gly Asp Asp Cys Val Ala Ser Arg Gln 100 105 110 Asp Glu Asp 115 77 33 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 77 tataggatcc taatcctcat cctgtctact tgc 33 78 770 DNA Artificial Sequence Description of Artificial Sequence Synthetic oligonucleotide 78 catatgtttt tagatggaat agataaggcc caagatgaac atgagaaata tcacagtaat 60 tggagagcaa tggctagtga ttttaacctg ccacctgggc ccaaaaaggc ccgtcgcatc 120 aagggcaaaa tgcgacgggt gaagaaagcc ggcgtagtag caaaagaaat agtagccagc 180 tgtgataaat gtcagctaaa aggagaagcc atgcatggac aagtagactg tagtccagga 240 atatggcaac tagattgtac acatttagaa ggaaaagtta tcctggtagc agttcatgta 300 gccagtggat atatagaagc agaagttatt ccagcagaaa cagggcagga aacagcatat 360 ggagcatgca tcaaacaccg ctacaagcga cgcgatcgtc ggaagcataa agtggcctgc 420 ctaggtcaaa tggcagtatt catccacaat tttaaaagaa aaggggggat tggggggtac 480 agtgcagggg aaagaatagt agacataata gcaacagaca tacaaactaa agaattacaa 540 aaacaaatta caaaaattca aaattttcgg gtttattaca gggacagcag aaatccactt 600 tggaaaggac cagcaaagct cctctggaaa ggtgaagggg cagtagtaat acaagataat 660 agtgacataa aagtagtgcc aagaagaaaa gcaaagatca ttagggatta tggaaaacag 720 atggcaggtg atgattgtgt ggcaagtaga caggatgagg attaggatcc 770 79 253 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 79 Met Phe Leu Asp Gly Ile Asp Lys Ala Gln Asp Glu His Glu Lys Tyr 1 5 10 15 His Ser Asn Trp Arg Ala Met Ala Ser Asp Phe Asn Leu Pro Pro Gly 20 25 30 Pro Lys Lys Ala Arg Arg Ile Lys Gly Lys Met Arg Arg Val Lys Lys 35 40 45 Ala Gly Val Val Ala Lys Glu Ile Val Ala Ser Cys Asp Lys Cys Gln 50 55 60 Leu Lys Gly Glu Ala Met His Gly Gln Val Asp Cys Ser Pro Gly Ile 65 70 75 80 Trp Gln Leu Asp Cys Thr His Leu Glu Gly Lys Val Ile Leu Val Ala 85 90 95 Val His Val Ala Ser Gly Tyr Ile Glu Ala Glu Val Ile Pro Ala Glu 100 105 110 Thr Gly Gln Glu Thr Ala Tyr Gly Ala Cys Ile Lys His Arg Tyr Lys 115 120 125 Arg Arg Asp Arg Arg Lys His Lys Val Ala Cys Ile Gly Gln Met Ala 130 135 140 Val Phe Ile His Asn Phe Lys Arg Lys Gly Gly Ile Gly Gly Tyr Ser 145 150 155 160 Ala Gly Glu Arg Ile Val Asp Ile Ile Ala Thr Asp Ile Gln Thr Lys 165 170 175 Glu Leu Gln Lys Gln Ile Thr Lys Ile Gln Asn Phe Arg Val Tyr Tyr 180 185 190 Arg Asp Ser Arg Asn Pro Leu Trp Lys Gly Pro Ala Lys Leu Leu Trp 195 200 205 Lys Gly Glu Gly Ala Val Val Ile Gln Asp Asn Ser Asp Ile Lys Val 210 215 220 Val Pro Arg Arg Lys Ala Lys Ile Ile Arg Asp Tyr Gly Lys Gln Met 225 230 235 240 Ala Gly Asp Asp Cys Val Ala Ser Arg Gln Asp Glu Asp 245 250 80 6 PRT Artificial Sequence Description of Artificial Sequence Synthetic 6X His tag 80 His His His His His His 1 5 81 232 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 81 Met Gly Ser Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr 1 5 10 15 Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys 20 25 30 Arg Arg Val Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ser Arg 35 40 45 Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg Ala 50 55 60 Ile Glu Ala Gln Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile Lys 65 70 75 80 Gln Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu Lys Asp Gln 85 90 95 Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr 100 105 110 Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile 115 120 125 Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile Asn Asn Tyr 130 135 140 Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln Glu 145 150 155 160 Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp 165 170 175 Asn Trp Phe Asn Ile Thr Asn Trp Leu Ala Met Glu Lys Tyr Leu Lys 180 185 190 Asp Gln Ala Arg Leu Asn Ser Trp Gly Cys Ala Phe Arg Gln Val Cys 195 200 205 His Asp Arg Pro Glu Gly Ile Glu Glu Glu Gly Gly Glu Arg Asp Arg 210 215 220 Asp Arg Ser Ile Arg Leu Val Asn 225 230 82 254 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 82 Met Gly Ser Asp Met Arg Asp Asn Trp Ile Gln Asn Gln Gln Leu Leu 1 5 10 15 Asn Leu Trp Gly Cys Lys Gly Arg Leu Val Cys Tyr Thr Asn Trp Arg 20 25 30 Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val 35 40 45 Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala 50 55 60 Val Gly Ile Gly Ser Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln 65 70 75 80 Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu 85 90 95 Thr Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu 100 105 110 Arg Tyr Leu Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly 115 120 125 Lys Leu Ile Cys Thr Thr Ala Val Pro Trp Asn Ala Ser Trp Ser Asn 130 135 140 Lys Ser Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp 145 150 155 160 Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu 165 170 175 Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp 180 185 190 Lys Trp Ala Ser Leu Trp Asn Trp Phe Asn Ile Thr Asn Trp Leu Ala 195 200 205 Met Glu Lys Tyr Leu Lys Asp Gln Ala Arg Leu Asn Ser Trp Gly Cys 210 215 220 Ala Phe Arg Gln Val Cys His Asp Arg Pro Glu Gly Ile Glu Glu Glu 225 230 235 240 Gly Gly Glu Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn 245 250 83 297 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 83 Met Gly Lys Arg Ala His Lys Ser Arg Lys Ile Lys Arg Val Thr Arg 1 5 10 15 Arg Gly Ala Val Gly Ile Gly Ile Asn Cys Thr Arg Pro Asn Asn Asn 20 25 30 Thr Arg Lys Ser Val Arg Ile Gly Pro Gly Gln Ala Phe Tyr Ala Thr 35 40 45 Gly Asp Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Ile Gly Pro 50 55 60 Thr Pro Thr Gly Trp Lys Lys Asn Arg Arg Leu Lys Gly Lys Tyr Arg 65 70 75 80 Arg Met Lys Lys Trp Gly Ala Val Gly Ile Gly Ile Asn Cys Thr Arg 85 90 95 Pro Asn Asn Asn His Thr Arg Lys Ser Ile His Ile Gly Pro Gly Arg 100 105 110 Ala Phe Tyr Ala Thr Ser Gly Asp Ile Ile Gly Asp Ile Arg Gln Ala 115 120 125 His Cys Asn Ile Gly Pro Thr Pro Thr Gly Ala Cys Val Lys His Arg 130 135 140 Gln Lys Arg Lys Glu Lys Arg Lys Tyr Lys Thr Ala Cys Val Gly Ala 145 150 155 160 Val Gly Ile Gly Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys 165 170 175 Ser Ile His Leu Gly Pro Gly Gln Ala Phe Tyr Ala Thr Gly Asp Gly 180 185 190 Asp Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Ile Gly Pro Thr 195 200 205 Pro Thr Gly Ser Lys Lys Ala Arg Arg Ile Lys Gly Lys Met Arg Arg 210 215 220 Leu Lys Lys Val Gly Ala Val Gly Ile Gly Ile Asn Cys Thr Arg Pro 225 230 235 240 Asn Asn Asn Gly His Thr Arg Lys Ser Ile Arg Ile Gly Pro Gly Gln 245 250 255 Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln Ala His 260 265 270 Cys Asn Ile Gly Pro Thr Pro Thr Gly Lys Arg Ala Val Lys Ser Arg 275 280 285 Lys Tyr Lys Arg His Ile Arg Arg Gly 290 295 84 221 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 84 Met Gly Ser Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr 1 5 10 15 Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys 20 25 30 Arg Arg Val Val Gln Arg Glu Ala Leu Glu Thr Leu Leu Gln Asn Gln 35 40 45 Gln Ile Leu Asn Leu Trp Gly Cys Lys Gly Arg Leu Ile Cys Tyr Trp 50 55 60 Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu Arg Tyr Leu 65 70 75 80 Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile 85 90 95 Cys Thr Thr Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu 100 105 110 Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile 115 120 125 Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn 130 135 140 Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala 145 150 155 160 Ser Leu Trp Asn Trp Phe Asn Ile Thr Asn Trp Leu Ala Ile Glu Lys 165 170 175 Tyr Leu Lys Asp Gln Ala Arg Leu Asn Ser Trp Gly Cys Ala Phe Arg 180 185 190 Gln Val Cys His Asp Arg Pro Glu Gly Ile Glu Glu Glu Gly Gly Glu 195 200 205 Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn Gly Ser 210 215 220 85 500 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 85 Met Gly Ala Arg Ala Ser Val Leu Ser Gly Gly Glu Leu Asp Arg Trp 1 5 10 15 Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys Lys Tyr Lys Leu Lys 20 25 30 His Ile Val Trp Ala Ser Arg Glu Leu Glu Arg Phe Ala Val Asn Pro 35 40 45 Gly Leu Leu Glu Thr Ser Glu Gly Cys Arg Gln Ile Leu Gly Gln Leu 50 55 60 Gln Pro Ser Leu Gln Thr Gly Ser Glu Glu Leu Arg Ser Leu Tyr Asn 65 70 75 80 Thr Val Ala Thr Leu Tyr Cys Val His Gln Arg Ile Glu Ile Lys Asp 85 90 95 Thr Lys Glu Ala Leu Asp Lys Ile Glu Glu Glu Gln Asn Lys Ser Lys 100 105 110 Lys Lys Ala Gln Gln Ala Ala Ala Asp Thr Gly His Ser Asn Gln Val 115 120 125 Ser Gln Asn Tyr Pro Ile Val Gln Asn Ile Gln Gly Gln Met Val His 130 135 140 Gln Ala Ile Ser Pro Arg Thr Leu Asn Ala Trp Val Lys Val Val Glu 145 150 155 160 Glu Lys Ala Phe Ser Pro Glu Val Ile Pro Met Phe Ser Ala Leu Ser 165 170 175 Glu Gly Ala Thr Pro Gln Asp Leu Asn Thr Met Leu Asn Thr Val Gly 180 185 190 Gly His Gln Ala Ala Met Gln Met Leu Lys Glu Thr Ile Asn Glu Glu 195 200 205 Ala Ala Glu Trp Asp Arg Val His Pro Val His Ala Gly Pro Ile Ala 210 215 220 Pro Gly Gln Met Arg Glu Pro Arg Gly Ser Asp Ile Ala Gly Thr Thr 225 230 235 240 Ser Thr Leu Gln Glu Gln Ile Gly Trp Met Thr Asn Asn Pro Pro Ile 245 250 255 Pro Val Gly Glu Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys 260 265 270 Ile Val Arg Met Tyr Ser Pro Thr Ser Ile Leu Asp Ile Arg Gln Gly 275 280 285 Pro Lys Glu Pro Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu 290 295 300 Arg Ala Glu Gln Ala Ser Gln Glu Val Lys Asn Trp Met Thr Glu Thr 305 310 315 320 Leu Leu Val Gln Asn Ala Asn Pro Asp Cys Lys Thr Ile Leu Lys Ala 325 330 335 Leu Gly Pro Ala Ala Thr Leu Glu Glu Met Met Thr Ala Cys Gln Gly 340 345 350 Val Gly Gly Pro Gly His Lys Ala Arg Val Leu Ala Glu Ala Met Ser 355 360 365 Gln Val Thr Asn Ser Ala Thr Ile Met Met Gln Arg Gly Asn Phe Arg 370 375 380 Asn Gln Arg Lys Ile Val Lys Cys Phe Asn Cys Gly Lys Glu Gly His 385 390 395 400 Thr Ala Arg Asn Cys Arg Ala Pro Arg Lys Lys Gly Cys Trp Lys Cys 405 410 415 Gly Lys Glu Gly His Gln Met Lys Asp Cys Thr Glu Arg Gln Ala Asn 420 425 430 Phe Leu Gly Lys Ile Trp Pro Ser Tyr Lys Gly Arg Pro Gly Asn Phe 435 440 445 Leu Gln Ser Arg Pro Glu Pro Thr Ala Pro Pro Glu Glu Ser Phe Arg 450 455 460 Ser Gly Val Glu Thr Thr Thr Pro Pro Gln Lys Gln Glu Pro Ile Asp 465 470 475 480 Lys Glu Leu Tyr Pro Leu Thr Ser Leu Arg Ser Leu Phe Gly Asn Asp 485 490 495 Pro Ser Ser Gln 500 86 696 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 86 Met Gly Ala Arg Ala Ser Val Leu Ser Gly Gly Glu Leu Asp Arg Trp 1 5 10 15 Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys Lys Tyr Lys Leu Lys 20 25 30 His Ile Val Trp Ala Ser Arg Glu Leu Glu Arg Phe Ala Val Asn Pro 35 40 45 Gly Leu Leu Glu Thr Ser Glu Gly Cys Arg Gln Ile Leu Gly Gln Leu 50 55 60 Gln Pro Ser Leu Gln Thr Gly Ser Glu Glu Leu Arg Ser Leu Tyr Asn 65 70 75 80 Thr Val Ala Thr Leu Tyr Cys Val His Gln Arg Ile Glu Ile Lys Asp 85 90 95 Thr Lys Glu Ala Leu Asp Lys Ile Glu Glu Glu Gln Asn Lys Ser Lys 100 105 110 Lys Lys Ala Gln Gln Ala Ala Ala Asp Thr Gly His Ser Asn Gln Val 115 120 125 Ser Gln Asn Tyr Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg 130 135 140 Xaa Xaa Arg Arg Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg 145 150 155 160 Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Pro Ile Val Gln Asn 165 170 175 Ile Gln Gly Gln Met Val His Gln Ala Ile Ser Pro Arg Thr Leu Asn 180 185 190 Ala Trp Val Lys Val Val Glu Glu Lys Ala Phe Ser Pro Glu Val Ile 195 200 205 Pro Met Phe Ser Ala Leu Ser Glu Gly Ala Thr Pro Gln Asp Leu Asn 210 215 220 Thr Met Leu Asn Thr Val Gly Gly His Gln Ala Ala Met Gln Met Leu 225 230 235 240 Lys Glu Thr Ile Asn Glu Glu Ala Ala Glu Trp Asp Arg Val His Pro 245 250 255 Val His Ala Gly Pro Ile Ala Pro Gly Gln Met Arg Glu Pro Arg Gly 260 265 270 Ser Asp Ile Ala Gly Thr Thr Ser Thr Leu Gln Glu Gln Ile Gly Trp 275 280 285 Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys 290 295 300 Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg 305 310 315 320 Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Met Thr Asn Asn Pro Pro Ile 325 330 335 Pro Val Gly Glu Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys 340 345 350 Ile Val Arg Met Tyr Ser Pro Thr Ser Ile Leu Asp Ile Arg Gln Gly 355 360 365 Pro Lys Glu Pro Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu 370 375 380 Arg Ala Glu Gln Ala Ser Gln Glu Val Lys Asn Trp Met Thr Glu Thr 385 390 395 400 Leu Leu Val Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa 405 410 415 Xaa Arg Arg Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa 420 425 430 Arg Arg Xaa Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys 435 440 445 Arg Arg Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Gln Asn Ala 450 455 460 Asn Pro Asp Cys Lys Thr Ile Leu Lys Ala Leu Gly Pro Ala Ala Thr 465 470 475 480 Leu Glu Glu Met Met Thr Ala Cys Gln Gly Val Gly Gly Pro Gly His 485 490 495 Lys Ala Arg Val Leu Ala Glu Ala Met Ser Gln Val Thr Asn Ser Ala 500 505 510 Thr Ile Met Met Gln Arg Gly Asn Phe Arg Asn Gln Arg Lys Ile Val 515 520 525 Lys Cys Phe Asn Cys Gly Lys Glu Gly His Thr Ala Arg Asn Cys Arg 530 535 540 Ala Pro Arg Lys Lys Gly Cys Trp Lys Cys Gly Lys Glu Gly His Gln 545 550 555 560 Met Lys Asp Cys Thr Glu Arg Gln Ala Asn Phe Leu Gly Lys Ile Trp 565 570 575 Pro Ser Tyr Lys Gly Arg Pro Gly Asn Phe Leu Gln Gly Lys Arg Xaa 580 585 590 Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly Xaa Lys 595 600 605 Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys Xaa Gly 610 615 620 Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg Lys Xaa 625 630 635 640 Lys Xaa Xaa Cys Xaa Gly Ser Arg Pro Glu Pro Thr Ala Pro Pro Glu 645 650 655 Glu Ser Phe Arg Ser Gly Val Glu Thr Thr Thr Pro Pro Gln Lys Gln 660 665 670 Glu Pro Ile Asp Lys Glu Leu Tyr Pro Leu Thr Ser Leu Arg Ser Leu 675 680 685 Phe Gly Asn Asp Pro Ser Ser Gln 690 695 87 561 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 87 Met Pro Ile Ser Pro Ile Glu Thr Val Pro Val Lys Leu Lys Pro Gly 1 5 10 15 Met Asp Gly Pro Lys Val Lys Gln Trp Pro Leu Thr Glu Glu Lys Ile 20 25 30 Lys Ala Leu Val Glu Ile Cys Thr Glu Met Glu Lys Glu Gly Lys Ile 35 40 45 Ser Lys Ile Gly Pro Glu Asn Pro Tyr Asn Thr Pro Val Phe Ala Ile 50 55 60 Lys Lys Lys Asp Ser Thr Lys Trp Arg Lys Leu Val Asp Phe Arg Glu 65 70 75 80 Leu Asn Lys Arg Thr Gln Asp Phe Trp Glu Val Gln Leu Gly Ile Pro 85 90 95 His Pro Ala Gly Leu Lys Lys Lys Lys Ser Val Thr Val Leu Asp Val 100 105 110 Gly Asp Ala Tyr Phe Ser Val Pro Leu Asp Glu Asp Phe Arg Lys Tyr 115 120 125 Thr Ala Phe Thr Ile Pro Ser Ile Asn Asn Glu Thr Pro Gly Ile Arg 130 135 140 Tyr Gln Tyr Asn Val Leu Pro Gln Gly Trp Lys Gly Ser Pro Ala Ile 145 150 155 160 Phe Gln Ser Ser Met Thr Lys Ile Leu Glu Pro Phe Arg Lys Gln Asn 165 170 175 Pro Asn Ile Val Ile Tyr Gln Tyr Met Asp Asp Leu Tyr Val Gly Ser 180 185 190 Asp Leu Glu Ile Gly Gln His Arg Thr Lys Ile Glu Glu Leu Arg Gln 195 200 205 His Leu Leu Arg Trp Gly Leu Thr Thr Pro Asp Lys Lys His Gln Lys 210 215 220 Glu Pro Pro Phe Leu Trp Met Gly Tyr Glu Leu His Pro Asp Lys Trp 225 230 235 240 Thr Val Gln Pro Ile Val Leu Pro Glu Lys Asp Ser Trp Thr Val Asn 245 250 255 Asp Ile Gln Lys Leu Val Gly Lys Leu Asn Trp Ala Ser Gln Ile Tyr 260 265 270 Pro Gly Ile Lys Val Arg Gln Leu Cys Lys Leu Leu Arg Gly Thr Lys 275 280 285 Ala Leu Thr Glu Val Ile Pro Leu Thr Glu Glu Ala Glu Leu Glu Leu 290 295 300 Ala Glu Asn Arg Glu Ile Leu Lys Glu Pro Val His Gly Val Tyr Tyr 305 310 315 320 Asp Pro Ser Lys Asp Leu Ile Ala Glu Ile Gln Lys Gln Gly Gln Gly 325 330 335 Gln Trp Thr Tyr Gln Ile Tyr Gln Glu Pro Phe Lys Asn Leu Lys Thr 340 345 350 Gly Lys Tyr Ala Arg Met Arg Gly Ala His Thr Asn Asp Val Lys Gln 355 360 365 Leu Thr Glu Ala Val Gln Lys Ile Thr Thr Glu Ser Ile Val Ile Trp 370 375 380 Gly Lys Thr Pro Lys Phe Lys Leu Pro Ile Gln Lys Glu Thr Trp Glu 385 390 395 400 Thr Trp Trp Thr Glu Tyr Trp Gln Ala Thr Trp Ile Pro Glu Trp Glu 405 410 415 Phe Val Asn Thr Pro Pro Leu Val Lys Leu Trp Tyr Gln Leu Glu Lys 420 425 430 Glu Pro Ile Val Gly Ala Glu Thr Phe Tyr Val Asp Gly Ala Ala Asn 435 440 445 Arg Glu Thr Lys Leu Gly Lys Ala Gly Tyr Val Thr Asn Arg Gly Arg 450 455 460 Gln Lys Val Val Thr Leu Thr Asp Thr Thr Asn Gln Lys Thr Glu Leu 465 470 475 480 Gln Ala Ile Tyr Leu Ala Leu Gln Asp Ser Gly Leu Glu Val Asn Ile 485 490 495 Val Thr Asp Ser Gln Tyr Ala Leu Gly Ile Ile Gln Ala Gln Pro Asp 500 505 510 Gln Ser Glu Ser Glu Leu Val Asn Gln Ile Ile Glu Gln Leu Ile Lys 515 520 525 Lys Glu Lys Val Tyr Leu Ala Trp Val Pro Ala His Lys Gly Ile Gly 530 535 540 Gly Asn Glu Gln Val Asp Lys Leu Val Ser Ala Gly Ile Arg Lys Val 545 550 555 560 Leu 88 851 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 88 Met Pro Ile Ser Pro Ile Glu Thr Val Pro Val Lys Leu Lys Pro Gly 1 5 10 15 Met Asp Gly Pro Lys Val Lys Gln Trp Pro Leu Thr Glu Glu Lys Ile 20 25 30 Lys Ala Leu Val Glu Ile Cys Thr Glu Met Glu Lys Glu Gly Lys Ile 35 40 45 Ser Lys Ile Gly Pro Glu Asn Pro Tyr Asn Thr Pro Val Gly Lys Arg 50 55 60 Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly Xaa 65 70 75 80 Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys Xaa 85 90 95 Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg Lys 100 105 110 Xaa Lys Xaa Xaa Cys Xaa Gly Phe Ala Ile Lys Lys Lys Asp Ser Thr 115 120 125 Lys Trp Arg Lys Leu Val Asp Phe Arg Glu Leu Asn Lys Arg Thr Gln 130 135 140 Asp Phe Trp Glu Val Gln Leu Gly Ile Pro His Pro Ala Gly Leu Lys 145 150 155 160 Lys Lys Lys Ser Val Thr Val Leu Asp Val Gly Asp Ala Tyr Phe Ser 165 170 175 Val Pro Leu Asp Glu Asp Phe Arg Lys Tyr Thr Ala Phe Thr Ile Pro 180 185 190 Ser Ile Asn Asn Glu Thr Pro Gly Ile Arg Tyr Gln Tyr Asn Val Leu 195 200 205 Pro Gln Gly Trp Lys Gly Ser Pro Ala Ile Phe Gln Ser Ser Met Thr 210 215 220 Lys Ile Leu Glu Pro Phe Arg Lys Gln Asn Pro Asn Ile Val Ile Tyr 225 230 235 240 Gln Tyr Met Asp Asp Leu Tyr Val Gly Ser Asp Leu Glu Ile Gly Gln 245 250 255 His Arg Thr Lys Ile Glu Glu Leu Arg Gln His Leu Leu Arg Trp Gly 260 265 270 Leu Thr Thr Pro Asp Lys Lys His Gln Lys Glu Pro Pro Phe Gly Lys 275 280 285 Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly 290 295 300 Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys 305 310 315 320 Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg 325 330 335 Lys Xaa Lys Xaa Xaa Cys Xaa Gly Leu Trp Met Gly Tyr Glu Leu His 340 345 350 Pro Asp Lys Trp Thr Val Gln Pro Ile Val Leu Pro Glu Lys Asp Ser 355 360 365 Trp Thr Val Asn Asp Ile Gln Lys Leu Val Gly Lys Leu Asn Trp Ala 370 375 380 Ser Gln Ile Tyr Pro Gly Ile Lys Val Arg Gln Leu Cys Lys Leu Leu 385 390 395 400 Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg 405 410 415 Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa 420 425 430 Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa 435 440 445 Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Arg Gly Thr Lys Ala Leu 450 455 460 Thr Glu Val Ile Pro Leu Thr Glu Glu Ala Glu Leu Glu Leu Ala Glu 465 470 475 480 Asn Arg Glu Ile Leu Lys Glu Pro Val His Gly Val Tyr Tyr Asp Pro 485 490 495 Ser Lys Asp Leu Ile Ala Glu Ile Gln Lys Gln Gly Gln Gly Gln Trp 500 505 510 Thr Tyr Gln Ile Tyr Gln Glu Pro Phe Lys Asn Leu Lys Thr Gly Lys 515 520 525 Tyr Ala Arg Met Arg Gly Ala His Thr Asn Asp Val Lys Gln Leu Thr 530 535 540 Glu Ala Val Gln Lys Ile Thr Thr Glu Ser Ile Val Ile Trp Gly Lys 545 550 555 560 Thr Pro Lys Phe Lys Leu Pro Ile Gln Lys Glu Thr Trp Glu Thr Trp 565 570 575 Trp Thr Glu Tyr Trp Gln Ala Thr Trp Ile Pro Glu Trp Glu Phe Val 580 585 590 Asn Thr Pro Pro Leu Val Lys Leu Trp Tyr Gln Leu Glu Lys Glu Pro 595 600 605 Ile Val Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa 610 615 620 Arg Arg Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg 625 630 635 640 Arg Xaa Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg 645 650 655 Arg Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Gly Ala Glu Thr 660 665 670 Phe Tyr Val Asp Gly Ala Ala Asn Arg Glu Thr Lys Leu Gly Lys Ala 675 680 685 Gly Tyr Val Thr Asn Arg Gly Arg Gln Lys Val Val Thr Leu Thr Asp 690 695 700 Thr Thr Asn Gln Lys Thr Glu Leu Gln Ala Ile Tyr Leu Ala Leu Gln 705 710 715 720 Asp Ser Gly Leu Glu Val Asn Ile Val Thr Asp Ser Gln Tyr Ala Leu 725 730 735 Gly Ile Ile Gln Ala Gln Pro Asp Gln Ser Glu Ser Glu Leu Val Asn 740 745 750 Gln Ile Ile Glu Gln Leu Ile Lys Lys Glu Lys Val Tyr Leu Ala Gly 755 760 765 Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly 770 775 780 Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys 785 790 795 800 Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg 805 810 815 Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Trp Val Pro Ala His Lys Gly 820 825 830 Ile Gly Gly Asn Glu Gln Val Asp Lys Leu Val Ser Ala Gly Ile Arg 835 840 845 Lys Val Leu 850 89 289 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 89 Met Phe Leu Asp Gly Ile Asp Lys Ala Gln Asp Glu His Glu Lys Tyr 1 5 10 15 His Ser Asn Trp Arg Ala Met Ala Ser Asp Phe Asn Leu Pro Pro Val 20 25 30 Val Ala Lys Glu Ile Val Ala Ser Cys Asp Lys Cys Gln Leu Lys Gly 35 40 45 Glu Ala Met His Gly Gln Val Asp Cys Ser Pro Gly Ile Trp Gln Leu 50 55 60 Asp Cys Thr His Leu Glu Gly Lys Val Ile Leu Val Ala Val His Val 65 70 75 80 Ala Ser Gly Tyr Ile Glu Ala Glu Val Ile Pro Ala Glu Thr Gly Gln 85 90 95 Glu Thr Ala Tyr Phe Leu Leu Lys Leu Ala Gly Arg Trp Pro Val Lys 100 105 110 Thr Ile His Thr Asp Asn Gly Ser Asn Phe Thr Ser Ala Thr Val Lys 115 120 125 Ala Ala Cys Trp Trp Ala Gly Ile Lys Gln Glu Phe Gly Ile Pro Tyr 130 135 140 Asn Pro Gln Ser Gln Gly Val Val Glu Ser Met Asn Lys Glu Leu Lys 145 150 155 160 Lys Ile Ile Gly Gln Val Arg Asp Gln Ala Glu His Leu Lys Thr Ala 165 170 175 Val Gln Met Ala Val Phe Ile His Asn Phe Lys Arg Lys Gly Gly Ile 180 185 190 Gly Gly Tyr Ser Ala Gly Glu Arg Ile Val Asp Ile Ile Ala Thr Asp 195 200 205 Ile Gln Thr Lys Glu Leu Gln Lys Gln Ile Thr Lys Ile Gln Asn Phe 210 215 220 Arg Val Tyr Tyr Arg Asp Ser Arg Asn Pro Leu Trp Lys Gly Pro Ala 225 230 235 240 Lys Leu Leu Trp Lys Gly Glu Gly Ala Val Val Ile Gln Asp Asn Ser 245 250 255 Asp Ile Lys Val Val Pro Arg Arg Lys Ala Lys Ile Ile Arg Asp Tyr 260 265 270 Gly Lys Gln Met Ala Gly Asp Asp Cys Val Ala Ser Arg Gln Asp Glu 275 280 285 Asp 90 521 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 90 Met Phe Leu Asp Gly Ile Asp Lys Ala Gln Asp Glu His Glu Lys Tyr 1 5 10 15 His Ser Asn Trp Arg Ala Met Ala Ser Asp Phe Asn Leu Pro Pro Gly 20 25 30 Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly 35 40 45 Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys 50 55 60 Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg 65 70 75 80 Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Val Val Ala Lys Glu Ile Val 85 90 95 Ala Ser Cys Asp Lys Cys Gln Leu Lys Gly Glu Ala Met His Gly Gln 100 105 110 Val Asp Cys Ser Pro Gly Ile Trp Gln Leu Asp Cys Thr His Leu Glu 115 120 125 Gly Lys Val Ile Leu Val Ala Val His Val Ala Ser Gly Tyr Ile Glu 130 135 140 Ala Glu Val Ile Pro Ala Glu Thr Gly Gln Glu Thr Ala Tyr Gly Lys 145 150 155 160 Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly 165 170 175 Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys 180 185 190 Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg 195 200 205 Lys Xaa Lys Xaa Xaa Cys Xaa Gly Phe Leu Leu Lys Leu Ala Gly Arg 210 215 220 Trp Pro Val Lys Thr Ile His Thr Asp Asn Gly Ser Asn Phe Thr Ser 225 230 235 240 Ala Thr Val Lys Ala Ala Cys Trp Trp Ala Gly Ile Lys Gln Glu Phe 245 250 255 Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg 260 265 270 Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa 275 280 285 Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa 290 295 300 Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Gly Ile Pro Tyr Asn Pro 305 310 315 320 Gln Ser Gln Gly Val Val Glu Ser Met Asn Lys Glu Leu Lys Lys Ile 325 330 335 Ile Gly Gln Val Arg Asp Gln Ala Glu His Leu Lys Thr Ala Val Gly 340 345 350 Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly 355 360 365 Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys 370 375 380 Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg 385 390 395 400 Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Gln Met Ala Val Phe Ile His 405 410 415 Asn Phe Lys Arg Lys Gly Gly Ile Gly Gly Tyr Ser Ala Gly Glu Arg 420 425 430 Ile Val Asp Ile Ile Ala Thr Asp Ile Gln Thr Lys Glu Leu Gln Lys 435 440 445 Gln Ile Thr Lys Ile Gln Asn Phe Arg Val Tyr Tyr Arg Asp Ser Arg 450 455 460 Asn Pro Leu Trp Lys Gly Pro Ala Lys Leu Leu Trp Lys Gly Glu Gly 465 470 475 480 Ala Val Val Ile Gln Asp Asn Ser Asp Ile Lys Val Val Pro Arg Arg 485 490 495 Lys Ala Lys Ile Ile Arg Asp Tyr Gly Lys Gln Met Ala Gly Asp Asp 500 505 510 Cys Val Ala Ser Arg Gln Asp Glu Asp 515 520 91 489 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 91 Met Asp Gly Ser His Gly Thr Glu Lys Leu Trp Val Thr Val Tyr Tyr 1 5 10 15 Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala Ser 20 25 30 Asp Ala Lys Ala Tyr Asp Thr Glu Val His Asn Val Trp Ala Thr His 35 40 45 Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Val Val Leu Val Asn 50 55 60 Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asp Met Val Glu Gln Met 65 70 75 80 His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro Cys Val 85 90 95 Lys Leu Thr Pro Leu Cys Val Ser Leu Lys Glu Cys Thr Asp Leu Lys 100 105 110 Asn Asp Thr Asn Thr Asn Ser Ser Ser Gly Arg Met Ile Met Glu Lys 115 120 125 Gly Glu Ile Lys Asn Cys Ser Asn Ile Ser Thr Ser Ile Arg Gly Lys 130 135 140 Val Gln Lys Glu Tyr Ala Phe Phe Tyr Lys Leu Asp Ile Ile Pro Ile 145 150 155 160 Asp Asn Asp Thr Thr Ser Tyr Lys Leu Thr Ser Cys Asn Thr Ser Val 165 170 175 Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His 180 185 190 Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asn Lys Thr 195 200 205 Phe Asn Gly Thr Gly Pro Cys Thr Asn Val Ser Thr Val Gln Cys Thr 210 215 220 His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser 225 230 235 240 Leu Ala Glu Glu Glu Val Val Ile Arg Ser Val Asn Phe Thr Asp Asn 245 250 255 Ala Lys Thr Ile Ile Val Gln Leu Asn Thr Ser Val Glu Ile Asn Cys 260 265 270 Thr Arg Pro Asn Asn Asn Thr Arg Lys Arg Ile Arg Ile Gln Arg Gly 275 280 285 Pro Gly Arg Ala Phe Val Thr Ile Gly Lys Ile Gly Asn Met Arg Gln 290 295 300 Ala His Cys Asn Ile Ser Arg Ala Lys Trp Asn Asn Thr Leu Lys Gln 305 310 315 320 Ile Ala Ser Lys Leu Arg Glu Gln Phe Gly Asn Asn Lys Thr Ile Ile 325 330 335 Phe Lys Gln Ser Ser Gly Gly Asp Pro Glu Ile Val Thr His Ser Phe 340 345 350 Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Ser Thr Gln Leu Phe Asn 355 360 365 Ser Thr Trp Phe Asn Ser Thr Trp Ser Thr Glu Gly Ser Asn Asn Thr 370 375 380 Glu Gly Ser Asp Leu Gln Thr Ile Thr Leu Pro Cys Arg Ile Lys Gln 385 390 395 400 Ile Ile Asn Met Trp Gln Lys Val Gly Lys Ala Met Tyr Ala Pro Pro 405 410 415 Ile Ser Gly Gln Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu 420 425 430 Thr Arg Asp Gly Gly Asn Ser Asn Asn Glu Ser Glu Ile Phe Arg Pro 435 440 445 Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr 450 455 460 Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys 465 470 475 480 Arg Arg Val Val Gln Arg Glu Lys Arg 485 92 2679 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 92 Met Asp Gly Thr Arg Arg Ser Ile Ser Phe Gly Ile Gly Pro Gly Gln 1 5 10 15 Ala Leu Tyr Thr Thr Thr Met Lys Arg Thr Ser Ile His Ile Gly Pro 20 25 30 Gly Gln Thr Phe Tyr Ala Thr Thr Val Gln Glu Ile Arg Ile Gly Pro 35 40 45 Met Ala Trp Tyr Ser Met Gly Asn Val Thr Arg Ile Ser His Thr Ile 50 55 60 Gly Pro Gly Arg Val Phe Tyr Arg Thr Thr Arg Lys Gly Ile His Met 65 70 75 80 Gly Pro Gly Gln Val Leu Tyr Ala Thr Lys Pro His Thr Arg Lys Ser 85 90 95 Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr Ser Thr Arg Lys 100 105 110 Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Thr Thr Ser Met Gln 115 120 125 Gln Thr Arg Thr Ser Ile Thr Ile Gly Pro Gly Gln Val Phe Tyr Arg 130 135 140 Thr Glu Gly Thr Arg Lys Ser Val Arg Ile Gly Pro Gly Gln Thr Phe 145 150 155 160 Tyr Ala Thr Gly Thr Arg Lys Gly Ile His Ile Gly Pro Gly Arg Ala 165 170 175 Phe Tyr Ala Thr Gly Ser His Gly Thr Glu Lys Leu Trp Val Thr Val 180 185 190 Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys 195 200 205 Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val His Asn Val Gly Lys 210 215 220 Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly 225 230 235 240 Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys 245 250 255 Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg 260 265 270 Lys Xaa Lys Xaa Xaa Cys Xaa Gly Trp Ala Thr His Ala Cys Val Pro 275 280 285 Thr Asp Pro Asn Pro Gln Glu Val Val Leu Val Asn Val Thr Glu Asn 290 295 300 Phe Asn Met Trp Lys Asn Asp Thr Arg Lys Ser Ile His Ile Gly Pro 305 310 315 320 Gly Gln Ala Phe Tyr Ala Thr Gly Asp Thr Arg Arg Ser Ile Ser Phe 325 330 335 Gly Ile Gly Pro Gly Gln Ala Leu Tyr Thr Thr Thr Arg Gln Arg Thr 340 345 350 Pro Ile Gly Leu Gly Gln Ala Leu Tyr Thr Thr Gly Gln Phe Arg Thr 355 360 365 Val Gln Glu Ile Arg Ile Gly Pro Met Ala Trp Tyr Ser Met Gly Ala 370 375 380 Thr Met Lys Arg Thr Ser Ile His Ile Gly Pro Gly Gln Thr Phe Tyr 385 390 395 400 Ala Thr Thr Arg Arg Gly Ile Pro Leu Gly Pro Gly Arg Ala Trp Tyr 405 410 415 Ala Thr Leu Asp Ser Thr Arg Glu Ser Met Arg Ile Gly Pro Gly Gln 420 425 430 Ala Phe Tyr Ala Thr Gly Ile Arg Gln Gly Ile His Ile Gly Pro Gly 435 440 445 Arg Ala Phe Phe Ala Ala Trp Thr Arg Lys Ser Val Arg Ile Gly Pro 450 455 460 Gly Gln Ala Phe Tyr Ala Thr Thr Arg Lys Ser Ile His Leu Gly Pro 465 470 475 480 Gly Gln Ala Phe Tyr Ala Thr Gly Asp Thr Arg Lys Gly Ile His Met 485 490 495 Gly Pro Gly Gln Val Leu Tyr Ala Thr Lys Pro Met Val Glu Gln Met 500 505 510 His Glu Asp Ile Ile Ser Leu Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys 515 520 525 Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa 530 535 540 Lys Gly Lys Xaa Arg Arg Xaa Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys 545 550 555 560 Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa 565 570 575 Gly Trp Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys 580 585 590 Val Ser Leu Lys Glu Cys Thr Asp Leu Lys Asn Asp Thr Asn Thr Asn 595 600 605 Ser Ser Ser Gly Arg Met Ile Met Glu Lys Gly Glu Ile Lys Asn Cys 610 615 620 Ser Phe Thr Arg Lys Ser Ile His Ile Gly Pro Gly Gln Ala Phe Tyr 625 630 635 640 Ala Thr Gly Asp Thr Arg Arg Ser Ile Ser Phe Gly Ile Gly Pro Gly 645 650 655 Gln Ala Leu Tyr Thr Thr Thr Arg Gln Arg Thr Pro Ile Gly Leu Gly 660 665 670 Gln Ala Leu Tyr Thr Thr Gly Gln Phe Arg Thr Val Gln Glu Ile Arg 675 680 685 Ile Gly Pro Met Ala Trp Tyr Ser Met Gly Ala Thr Met Lys Arg Thr 690 695 700 Ser Ile His Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Thr Arg Arg 705 710 715 720 Gly Ile Pro Leu Gly Pro Gly Arg Ala Trp Tyr Ala Thr Leu Asp Ser 725 730 735 Thr Arg Glu Ser Met Arg Ile Gly Pro Gly Gln Ala Phe Tyr Ala Thr 740 745 750 Gly Ile Arg Gln Gly Ile His Ile Gly Pro Gly Arg Ala Phe Phe Ala 755 760 765 Ala Trp Asp Val Gln Glu Met Arg Ile Gly Pro Met Ala Trp Tyr Ser 770 775 780 Met Gly Ile Cys Thr Arg Arg Gly Ile Arg Met Gly Pro Gly Gln Val 785 790 795 800 Val Tyr Ala Thr Cys Thr Thr Ile Val Gln Ile Lys Ile Ile Gly Pro 805 810 815 Leu Ala Val Tyr Ser Met Tyr Gly Thr Arg Lys Ser Val Arg Ile Gly 820 825 830 Pro Gly Gln Ala Phe Tyr Ala Thr Gly His Thr Arg Lys Ser Ile Arg 835 840 845 Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Asn Thr Arg Gln Ser Thr 850 855 860 His Ile Gly Pro Gly Ala Leu Tyr Thr Thr Lys Ile Glu Thr Arg Lys 865 870 875 880 Ser Ile His Leu Gly Pro Gly Gln Ala Phe Tyr Ala Thr Gly Asp Tyr 885 890 895 Gln Thr Arg Lys Ser Ile Arg Ile Gly Pro Gly Gln Ala Phe Tyr Ala 900 905 910 Thr Gly Asp Thr Val Gln Glu Ile Arg Ile Gly Pro Met Ala Trp Tyr 915 920 925 Ser Met Gly Asn Val Thr Arg Ile Ser His Thr Ile Gly Pro Gly Arg 930 935 940 Val Phe Tyr Arg Thr Thr Arg Lys Gly Ile His Met Gly Pro Gly Gln 945 950 955 960 Val Leu Tyr Ala Thr Lys Pro His Thr Arg Lys Ser Ile His Ile Gly 965 970 975 Pro Gly Arg Ala Phe Tyr Ala Thr Ser Thr Arg Lys Ser Ile His Ile 980 985 990 Gly Pro Gly Arg Ala Phe Tyr Thr Thr Ser Met Gln Gln Thr Arg Thr 995 1000 1005 Ser Ile Thr Ile Gly Pro Gly Gln Val Phe Tyr Arg Thr Glu Gly Thr 1010 1015 1020 Arg Lys Ser Val Arg Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Gly 1025 1030 1035 1040 Thr Arg Lys Gly Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr 1045 1050 1055 Gly Pro Thr Arg Lys Ser Ile His Ile Gly Pro Gly Gln Ala Phe Tyr 1060 1065 1070 Ala Thr Gly Asp Thr Arg Arg Ser Ile Ser Phe Gly Ile Gly Pro Gly 1075 1080 1085 Gln Ala Leu Tyr Thr Thr Thr Arg Gln Arg Thr Pro Ile Gly Leu Gly 1090 1095 1100 Gln Ala Leu Tyr Thr Thr Gly Gln Phe Arg Thr Val Gln Glu Ile Arg 1105 1110 1115 1120 Ile Gly Pro Met Ala Trp Tyr Ser Met Gly Ala Thr Met Lys Arg Thr 1125 1130 1135 Ser Ile His Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Thr Arg Arg 1140 1145 1150 Gly Ile Pro Leu Gly Pro Gly Arg Ala Trp Tyr Ala Thr Leu Asp Ser 1155 1160 1165 Thr Arg Glu Ser Met Arg Ile Gly Pro Gly Gln Ala Phe Tyr Ala Thr 1170 1175 1180 Gly Ile Arg Gln Gly Ile His Ile Gly Pro Gly Arg Ala Phe Phe Ala 1185 1190 1195 1200 Ala Trp Asp Val Gln Glu Met Arg Ile Gly Pro Met Ala Trp Tyr Ser 1205 1210 1215 Met Gly Ile Cys Thr Arg Arg Gly Ile Arg Met Gly Pro Gly Gln Val 1220 1225 1230 Val Tyr Ala Thr Cys Thr Thr Ile Val Gln Ile Lys Ile Ile Gly Pro 1235 1240 1245 Leu Ala Val Tyr Ser Met Tyr Gly Thr Arg Lys Ser Val Arg Ile Gly 1250 1255 1260 Pro Gly Gln Ala Phe Tyr Ala Thr Gly His Thr Arg Lys Ser Ile Arg 1265 1270 1275 1280 Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Gly Thr Arg Lys Ser Val 1285 1290 1295 Arg Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Gly Asn Ile Ser Thr 1300 1305 1310 Ser Ile Arg Gly Lys Val Gln Lys Glu Tyr Ala Phe Phe Tyr Lys Leu 1315 1320 1325 Asp Ile Ile Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa 1330 1335 1340 Xaa Arg Arg Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa 1345 1350 1355 1360 Arg Arg Xaa Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys 1365 1370 1375 Arg Arg Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Pro Ile Asp 1380 1385 1390 Asn Asp Thr Thr Ser Tyr Lys Leu Thr Ser Cys Asn Thr Ser Val Ile 1395 1400 1405 Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr 1410 1415 1420 Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asn Lys Thr Phe 1425 1430 1435 1440 Asn Gly Thr Thr Arg Lys Ser Ile His Ile Gly Pro Gly Gln Ala Phe 1445 1450 1455 Tyr Ala Thr Gly Asp Thr Arg Arg Ser Ile Ser Phe Gly Ile Gly Pro 1460 1465 1470 Gly Gln Ala Leu Tyr Thr Thr Thr Arg Gln Arg Thr Pro Ile Gly Leu 1475 1480 1485 Gly Gln Ala Leu Tyr Thr Thr Gly Gln Phe Arg Thr Val Gln Glu Ile 1490 1495 1500 Arg Ile Gly Pro Met Ala Trp Tyr Ser Met Gly Ala Thr Met Lys Arg 1505 1510 1515 1520 Thr Ser Ile His Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Thr Arg 1525 1530 1535 Arg Gly Ile Pro Leu Gly Pro Gly Arg Ala Trp Tyr Ala Thr Leu Thr 1540 1545 1550 Ile Val Gln Ile Lys Ile Ile Gly Pro Leu Ala Val Tyr Ser Met Tyr 1555 1560 1565 Gly Thr Arg Lys Ser Val Arg Ile Gly Pro Gly Gln Ala Phe Tyr Ala 1570 1575 1580 Thr Gly His Thr Arg Lys Ser Ile Arg Ile Gly Pro Gly Gln Thr Phe 1585 1590 1595 1600 Tyr Ala Thr Asn Thr Arg Gln Ser Thr His Ile Gly Pro Gly Ala Leu 1605 1610 1615 Tyr Thr Thr Lys Ile Glu Thr Arg Lys Ser Ile His Leu Gly Pro Gly 1620 1625 1630 Gln Ala Phe Tyr Ala Thr Gly Asp Tyr Gln Thr Arg Lys Ser Ile Arg 1635 1640 1645 Ile Gly Pro Gly Gln Ala Phe Tyr Ala Thr Gly Asp Thr Val Gln Glu 1650 1655 1660 Ile Arg Ile Gly Pro Met Ala Trp Tyr Ser Met Gly Asn Val Thr Arg 1665 1670 1675 1680 Ile Ser His Thr Ile Gly Pro Gly Arg Val Phe Tyr Arg Thr Thr Arg 1685 1690 1695 Lys Gly Ile His Met Gly Pro Gly Gln Val Leu Tyr Ala Thr Lys Pro 1700 1705 1710 His Thr Arg Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala 1715 1720 1725 Thr Ser Thr Arg Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr 1730 1735 1740 Thr Thr Ser Met Gln Gln Thr Arg Thr Ser Ile Thr Ile Gly Pro Gly 1745 1750 1755 1760 Gln Val Phe Tyr Arg Thr Glu Gly Thr Arg Lys Ser Val Arg Ile Gly 1765 1770 1775 Pro Gly Gln Thr Phe Tyr Ala Thr Gly Thr Arg Lys Gly Ile His Ile 1780 1785 1790 Gly Pro Gly Arg Ala Phe Tyr Ala Thr Gly Gly Pro Cys Thr Asn Val 1795 1800 1805 Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln 1810 1815 1820 Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val Ile Arg Ser 1825 1830 1835 1840 Val Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg 1845 1850 1855 Arg Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg 1860 1865 1870 Xaa Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg 1875 1880 1885 Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Asn Phe Thr Asp Asn 1890 1895 1900 Ala Lys Thr Ile Ile Val Gln Leu Asn Thr Ser Val Glu Ile Asn Cys 1905 1910 1915 1920 Thr Arg Pro Asn Asn Asn Thr Arg Lys Arg Ile Arg Ile Gln Arg Gly 1925 1930 1935 Pro Gly Arg Ala Phe Val Thr Ile Gly Lys Ile Gly Asn Met Arg Gln 1940 1945 1950 Ala His Cys Asn Ile Ser Arg Ala Lys Trp Asn Asn Thr Leu Lys Gln 1955 1960 1965 Ile Ala Ser Lys Leu Arg Glu Gln Phe Gly Asn Asn Lys Thr Ile Ile 1970 1975 1980 Phe Lys Gln Ser Ser Gly Gly Asp Pro Glu Ile Val Thr His Ser Phe 1985 1990 1995 2000 Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Ser Thr Gln Leu Phe Asn 2005 2010 2015 Ser Thr Trp Phe Asn Ser Thr Trp Ser Thr Glu Gly Ser Asn Asn Thr 2020 2025 2030 Glu Gly Ser Asp Leu Gln Thr Arg Lys Ser Ile His Ile Gly Pro Gly 2035 2040 2045 Gln Ala Phe Tyr Ala Thr Gly Asp Thr Arg Arg Ser Ile Ser Phe Gly 2050 2055 2060 Ile Gly Pro Gly Gln Ala Leu Tyr Thr Thr Thr Arg Gln Arg Thr Pro 2065 2070 2075 2080 Ile Gly Leu Gly Gln Ala Leu Tyr Thr Thr Gly Gln Phe Arg Thr Val 2085 2090 2095 Gln Glu Ile Arg Ile Gly Pro Met Ala Trp Tyr Ser Met Gly Ala Thr 2100 2105 2110 Met Lys Arg Thr Ser Ile His Ile Gly Pro Gly Gln Thr Phe Tyr Ala 2115 2120 2125 Thr Thr Arg Arg Gly Ile Pro Leu Gly Pro Gly Arg Ala Trp Tyr Ala 2130 2135 2140 Thr Leu Asp Ser Thr Arg Glu Ser Met Arg Ile Gly Pro Gly Gln Ala 2145 2150 2155 2160 Phe Tyr Ala Thr Gly Ile Arg Gln Gly Ile His Ile Gly Pro Gly Arg 2165 2170 2175 Ala Phe Phe Ala Ala Trp Asp Val Gln Glu Met Arg Ile Gly Pro Met 2180 2185 2190 Ala Trp Tyr Ser Met Gly Ile Cys Thr Arg Arg Gly Ile Arg Met Gly 2195 2200 2205 Pro Gly Gln Val Val Tyr Ala Thr Cys Thr Thr Ile Val Gln Ile Lys 2210 2215 2220 Ile Ile Gly Pro Leu Ala Val Tyr Ser Met Tyr Gly Thr Arg Lys Ser 2225 2230 2235 2240 Val Arg Ile Gly Pro Gly Gln Ala Phe Tyr Ala Thr Gly His Thr Arg 2245 2250 2255 Lys Ser Ile Arg Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Asn Thr 2260 2265 2270 Arg Gln Ser Thr His Ile Gly Pro Gly Ala Leu Tyr Thr Thr Lys Ile 2275 2280 2285 Glu Thr Arg Lys Ser Ile His Leu Gly Pro Gly Gln Ala Phe Tyr Ala 2290 2295 2300 Thr Gly Asp Tyr Gln Thr Arg Lys Ser Ile Arg Ile Gly Pro Gly Gln 2305 2310 2315 2320 Ala Phe Tyr Ala Thr Gly Asp Thr Val Gln Glu Ile Arg Ile Gly Pro 2325 2330 2335 Met Ala Trp Tyr Ser Met Gly Asn Val Thr Arg Ile Ser His Thr Ile 2340 2345 2350 Gly Pro Gly Arg Val Phe Tyr Arg Thr Thr Arg Lys Gly Ile His Met 2355 2360 2365 Gly Pro Gly Gln Val Leu Tyr Ala Thr Lys Pro His Thr Arg Lys Ser 2370 2375 2380 Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr Ser Thr Arg Lys 2385 2390 2395 2400 Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Thr Thr Ser Met Gln 2405 2410 2415 Gln Thr Arg Thr Ser Ile Thr Ile Gly Pro Gly Gln Val Phe Tyr Arg 2420 2425 2430 Thr Glu Gly Thr Arg Lys Ser Val Arg Ile Gly Pro Gly Gln Thr Phe 2435 2440 2445 Tyr Ala Thr Gly Thr Arg Lys Gly Ile His Ile Gly Pro Gly Arg Ala 2450 2455 2460 Phe Tyr Ala Thr Gly Thr Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile 2465 2470 2475 2480 Ile Asn Met Trp Gln Lys Val Gly Lys Ala Met Tyr Ala Pro Gly Lys 2485 2490 2495 Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly 2500 2505 2510 Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys 2515 2520 2525 Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg 2530 2535 2540 Lys Xaa Lys Xaa Xaa Cys Xaa Gly Pro Ile Ser Gly Gln Ile Arg Cys 2545 2550 2555 2560 Ser Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Ser 2565 2570 2575 Asn Asn Glu Ser Glu Ile Phe Arg Pro Gly Gly Asp Ser Thr Arg Glu 2580 2585 2590 Ser Met Arg Ile Gly Pro Gly Gln Ala Phe Tyr Ala Thr Gly Asp Val 2595 2600 2605 Gln Glu Met Arg Ile Gly Pro Met Ala Trp Tyr Ser Met Gly Gln Thr 2610 2615 2620 Arg Thr Ser Ile Thr Ile Gly Pro Gly Gln Val Phe Tyr Arg Thr Glu 2625 2630 2635 2640 Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val 2645 2650 2655 Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys Arg Arg 2660 2665 2670 Val Val Gln Arg Glu Lys Arg 2675 93 391 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 93 Met Gly Ser Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr 1 5 10 15 Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys 20 25 30 Arg Arg Val Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ser Ala 35 40 45 Leu Phe Leu Gly Phe Leu Gly Ala Ala Gly Ser Thr Met Gly Ala Ala 50 55 60 Ser Met Thr Leu Thr Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val 65 70 75 80 Gln Gln Gln Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu 85 90 95 Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu 100 105 110 Ala Val Glu Arg Tyr Leu Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly 115 120 125 Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala Val Pro Trp Asn Ala Ser 130 135 140 Trp Ser Asn Lys Ser Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met 145 150 155 160 Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu 165 170 175 Ile Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu 180 185 190 Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe Asn Ile Thr Asn 195 200 205 Trp Leu Glu Phe Asn Asn Trp Tyr Ile Lys Leu Phe Ile Met Ile Val 210 215 220 Gly Gly Leu Val Gly Leu Arg Ile Val Phe Ala Val Leu Ser Ile Val 225 230 235 240 Asn Arg Val Arg Gln Gly Tyr Ser Pro Leu Ser Phe Gln Thr His Leu 245 250 255 Pro Ile Pro Arg Gly Pro Asp Arg Pro Glu Gly Ile Glu Glu Glu Gly 260 265 270 Gly Glu Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn Gly Ser Leu 275 280 285 Ala Leu Ile Trp Asp Asp Leu Arg Ser Leu Cys Leu Phe Ser Tyr His 290 295 300 Arg Leu Arg Asp Leu Leu Leu Ile Val Thr Arg Ile Val Glu Leu Leu 305 310 315 320 Gly Arg Arg Gly Trp Glu Ala Leu Lys Tyr Trp Trp Asn Leu Leu Gln 325 330 335 Tyr Trp Ser Gln Glu Leu Lys Asn Ser Ala Val Ser Leu Leu Asn Ala 340 345 350 Thr Ala Ile Ala Val Ala Glu Gly Thr Asp Arg Val Ile Glu Val Val 355 360 365 Gln Gly Ala Cys Arg Ala Ile Arg His Ile Pro Arg Arg Ile Arg Gln 370 375 380 Gly Leu Glu Arg Ile Leu Leu 385 390 94 1231 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 94 Met Gly Ser Asp Met Arg Asp Asn Gly Lys Arg Xaa Xaa Lys Xaa Arg 1 5 10 15 Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly Xaa Lys Lys Xaa Arg Arg 20 25 30 Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys Xaa Gly Trp Ile Gln Leu 35 40 45 Gln Gln Arg Leu Asn Leu Trp Gly Cys Arg Gly Lys Leu Ile Cys Tyr 50 55 60 Thr Asn Trp Ile Gln Asn Gln Gln Leu Leu Asn Leu Trp Gly Cys Lys 65 70 75 80 Gly Arg Leu Val Cys Tyr Thr Asn Trp Leu Gln Asn Gln Gln Ile Leu 85 90 95 Asn Leu Trp Gly Cys Lys Gly Arg Leu Ile Cys Tyr Thr Asn Trp Leu 100 105 110 Gln Ser Gln Gln Leu Leu Ser Asn Trp Gly Cys Arg Gly Lys Leu Val 115 120 125 Cys Tyr Thr Asn Ala Ile Glu Arg Tyr Leu Gln Asp Gln Ala Arg Leu 130 135 140 Asn Ser Trp Gly Cys Thr Phe Arg Gln Val Cys His Ala Met Glu Lys 145 150 155 160 Tyr Leu Lys Asp Gln Ala Arg Leu Asn Ser Trp Gly Cys Ala Phe Arg 165 170 175 Gln Val Cys His Ala Ile Glu Lys Tyr Leu Lys His Gln Ala Gln Leu 180 185 190 Asn Ala Trp Gly Cys Ala Phe Arg Gln Val Cys His Trp Arg Ser Glu 195 200 205 Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro 210 215 220 Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala Val Gly 225 230 235 240 Ile Gly Ser Ala Ile Glu Arg Tyr Leu Gln Asp Gln Ala Arg Leu Asn 245 250 255 Ser Trp Gly Cys Thr Phe Arg Gln Val Cys His Ala Met Glu Lys Tyr 260 265 270 Leu Arg Asp Gln Ala Ile Val Asn Ser Trp Gly Cys Ala Phe Arg Gln 275 280 285 Val Cys Tyr Ala Met Glu Lys Tyr Leu Lys Asp Gln Ala Arg Leu Asn 290 295 300 Ser Trp Gly Cys Ala Phe Arg Gln Val Cys His Ala Leu Phe Leu Gly 305 310 315 320 Phe Leu Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Met Thr Leu 325 330 335 Thr Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn 340 345 350 Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu Thr 355 360 365 Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Gly Lys Arg Xaa 370 375 380 Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly Xaa Lys 385 390 395 400 Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys Xaa Gly 405 410 415 Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg Lys Xaa 420 425 430 Lys Xaa Xaa Cys Xaa Gly Ala Val Glu Arg Tyr Leu Lys Asp Gln Gln 435 440 445 Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala 450 455 460 Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu Glu Gln Ile Trp 465 470 475 480 Asn Asn Met Thr Trp Met Glu Trp Ile Gln Leu Gln Gln Arg Leu Asn 485 490 495 Leu Trp Gly Cys Arg Gly Lys Leu Ile Cys Tyr Thr Asn Trp Leu Gln 500 505 510 Asn Gln Gln Ile Leu Asn Leu Trp Gly Cys Lys Gly Arg Leu Ile Cys 515 520 525 Tyr Thr Asn Trp Leu Gln Ser Gln Gln Leu Leu Ser Asn Trp Gly Cys 530 535 540 Arg Gly Lys Leu Val Cys Tyr Thr Asn Trp Asp Arg Glu Ile Asn Asn 545 550 555 560 Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln Gln 565 570 575 Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu 580 585 590 Trp Asn Trp Ile Gln Asn Gln Gln Leu Leu Asn Leu Trp Gly Cys Lys 595 600 605 Gly Arg Leu Val Cys Tyr Thr Asn Trp Leu Gln Asn Gln Gln Ile Leu 610 615 620 Asn Leu Trp Gly Cys Lys Gly Arg Leu Ile Cys Tyr Thr Asn Trp Phe 625 630 635 640 Asn Ile Thr Asn Trp Leu Glu Phe Asn Asn Trp Ile Gln Asn Gln Gln 645 650 655 Leu Leu Asn Leu Trp Gly Cys Lys Gly Arg Leu Val Cys Tyr Thr Asn 660 665 670 Trp Leu Gln Asn Gln Gln Ile Leu Asn Leu Trp Gly Cys Lys Gly Arg 675 680 685 Leu Ile Cys Tyr Thr Asn Trp Leu Gln Ser Gln Gln Leu Leu Ser Asn 690 695 700 Trp Gly Cys Arg Gly Lys Leu Val Cys Tyr Thr Asn Trp Gly Lys Arg 705 710 715 720 Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly Xaa 725 730 735 Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys Xaa 740 745 750 Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg Lys 755 760 765 Xaa Lys Xaa Xaa Cys Xaa Gly Ala Ile Glu Arg Tyr Leu Gln Asp Gln 770 775 780 Ala Arg Leu Asn Ser Trp Gly Cys Thr Phe Arg Gln Val Cys His Ala 785 790 795 800 Met Glu Lys Tyr Leu Arg Asp Gln Ala Ile Val Asn Ser Trp Gly Cys 805 810 815 Ala Phe Arg Gln Val Cys Tyr Ala Met Glu Lys Tyr Leu Lys Asp Gln 820 825 830 Ala Arg Leu Asn Ser Trp Gly Cys Ala Phe Arg Gln Val Cys His Ala 835 840 845 Ile Glu Lys Tyr Leu Lys His Gln Ala Gln Leu Asn Ala Trp Gly Cys 850 855 860 Ala Phe Arg Gln Val Cys His Trp Tyr Ile Lys Leu Phe Ile Met Ile 865 870 875 880 Val Gly Gly Leu Val Gly Leu Arg Ile Val Phe Ala Val Leu Ser Ile 885 890 895 Val Asn Arg Val Arg Gln Gly Tyr Ser Pro Leu Ser Phe Gln Thr His 900 905 910 Leu Pro Ile Pro Arg Gly Pro Asp Arg Pro Glu Gly Ile Glu Glu Glu 915 920 925 Gly Gly Glu Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn Ala Met 930 935 940 Glu Lys Tyr Leu Arg Asp Gln Ala Ile Val Asn Ser Trp Gly Cys Ala 945 950 955 960 Phe Arg Gln Val Cys Tyr Ala Met Glu Lys Tyr Leu Lys Asp Gln Ala 965 970 975 Arg Leu Asn Ser Trp Gly Cys Ala Phe Arg Gln Val Cys His Gly Ser 980 985 990 Leu Ala Leu Ile Trp Asp Asp Leu Arg Ser Leu Cys Leu Phe Ser Tyr 995 1000 1005 His Arg Leu Arg Asp Leu Leu Leu Ile Val Thr Arg Ile Val Glu Leu 1010 1015 1020 Leu Gly Arg Arg Gly Trp Glu Ala Leu Lys Tyr Trp Trp Asn Leu Leu 1025 1030 1035 1040 Gln Tyr Trp Ser Gln Glu Leu Lys Gly Lys Arg Xaa Xaa Lys Xaa Arg 1045 1050 1055 Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly Xaa Cys Xaa Lys Xaa Arg 1060 1065 1070 Xaa Lys Arg Arg Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Ala 1075 1080 1085 Ile Glu Arg Tyr Leu Gln Asp Gln Ala Arg Leu Asn Ser Trp Gly Cys 1090 1095 1100 Thr Phe Arg Gln Val Cys His Ala Met Glu Lys Tyr Leu Arg Asp Gln 1105 1110 1115 1120 Ala Ile Val Asn Ser Trp Gly Cys Ala Phe Arg Gln Val Cys Tyr Ala 1125 1130 1135 Met Glu Lys Tyr Leu Lys Asp Gln Ala Arg Leu Asn Ser Trp Gly Cys 1140 1145 1150 Ala Phe Arg Gln Val Cys His Ala Ile Glu Lys Tyr Leu Lys His Gln 1155 1160 1165 Ala Gln Leu Asn Ala Trp Gly Cys Ala Phe Arg Gln Val Cys His Asn 1170 1175 1180 Ser Ala Val Ser Leu Leu Asn Ala Thr Ala Ile Ala Val Ala Glu Gly 1185 1190 1195 1200 Thr Asp Arg Val Ile Glu Val Val Gln Gly Ala Cys Arg Ala Ile Arg 1205 1210 1215 His Ile Pro Arg Arg Ile Arg Gln Gly Leu Glu Arg Ile Leu Leu 1220 1225 1230 95 360 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 95 Met Met Ser Ser Ala His Gly Arg His Thr Arg Gly Val Phe Val Leu 1 5 10 15 Gly Phe Leu Gly Phe Leu Ala Thr Ala Gly Ser Ala Met Gly Ala Ala 20 25 30 Ser Leu Thr Val Ser Ala Gln Ser Arg Thr Leu Leu Ala Gly Ile Val 35 40 45 Gln Gln Gln Gln Gln Leu Leu Asp Val Val Lys Arg Gln Gln Glu Leu 50 55 60 Leu Arg Leu Thr Val Trp Gly Thr Lys Asn Leu Gln Ala Arg Val Thr 65 70 75 80 Ala Ile Glu Lys Tyr Leu Gln Asp Gln Ala Arg Leu Asn Ser Trp Gly 85 90 95 Cys Ala Phe Arg Gln Val Cys His Thr Thr Val Pro Trp Val Asn Asp 100 105 110 Ser Leu Ala Pro Asp Trp Asp Asn Met Thr Trp Gln Glu Trp Glu Lys 115 120 125 Gln Val Arg Tyr Leu Glu Ala Asn Ile Ser Lys Ser Leu Glu Gln Ala 130 135 140 Gln Ile Gln Gln Glu Lys Asn Met Tyr Glu Leu Gln Lys Leu Asn Ser 145 150 155 160 Trp Asp Ile Phe Gly Asn Trp Phe Asp Leu Thr Ser Trp Val Lys Asn 165 170 175 Tyr Ile Gln Tyr Gly Val Leu Ile Ile Val Ala Val Ile Ala Leu Arg 180 185 190 Ile Val Ile Tyr Val Val Gln Met Leu Ser Arg Leu Arg Lys Gly Tyr 195 200 205 Arg Pro Val Phe Ser Ser Pro Pro Gly Tyr Ile Gln Gln Ile His Ile 210 215 220 His Lys Asp Arg Gly Gln Ser Pro Ala Asn Glu Glu Thr Glu Glu Asp 225 230 235 240 Gly Gly Ser Asn Gly Gly Asp Arg Tyr Trp Pro Trp Pro Ile Ala Tyr 245 250 255 Ile His Phe Leu Ile Arg Gln Leu Ile Arg Leu Leu Thr Arg Leu Tyr 260 265 270 Ser Ile Cys Arg Asp Leu Leu Ser Arg Ser Phe Leu Thr Leu Gln Leu 275 280 285 Ile Tyr Gln Asn Leu Arg Asp Trp Leu Arg Leu Arg Thr Ala Phe Leu 290 295 300 Gln Tyr Gly Cys Glu Trp Ile Gln Glu Ala Phe Gln Ala Ala Ala Arg 305 310 315 320 Ala Thr Arg Glu Thr Leu Ala Gly Ala Cys Arg Gly Leu Trp Arg Val 325 330 335 Leu Glu Arg Ile Gly Arg Gly Ile Leu Ala Val Pro Arg Arg Ile Arg 340 345 350 Gln Gly Ala Glu Ile Ala Leu Leu 355 360 96 534 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 96 Met Met Ser Ser Ala His Gly Arg His Thr Arg Gly Val Phe Val Leu 1 5 10 15 Gly Phe Leu Gly Phe Leu Ala Thr Ala Gly Ser Ala Met Gly Ala Ala 20 25 30 Ser Leu Thr Val Ser Ala Gln Ser Arg Thr Leu Leu Ala Gly Ile Val 35 40 45 Gln Gln Gln Gln Gln Leu Leu Asp Val Val Lys Arg Gln Gln Glu Leu 50 55 60 Leu Arg Leu Thr Val Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys 65 70 75 80 Arg Xaa Xaa Arg Arg Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly 85 90 95 Lys Xaa Arg Arg Xaa Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg 100 105 110 Xaa Lys Arg Arg Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Trp 115 120 125 Gly Thr Lys Asn Leu Gln Ala Arg Val Thr Ala Ile Glu Lys Tyr Leu 130 135 140 Gln Asp Gln Ala Arg Leu Asn Ser Trp Gly Cys Ala Phe Arg Gln Val 145 150 155 160 Cys His Thr Thr Val Pro Trp Val Asn Asp Ser Leu Ala Pro Asp Trp 165 170 175 Asp Asn Met Thr Trp Gln Glu Trp Glu Lys Gln Val Arg Tyr Leu Glu 180 185 190 Ala Asn Ile Ser Lys Ser Leu Glu Gln Ala Gln Ile Gln Gln Glu Lys 195 200 205 Asn Met Tyr Glu Leu Gln Lys Leu Asn Ser Trp Asp Ile Phe Gly Asn 210 215 220 Trp Phe Asp Leu Thr Ser Trp Val Lys Asn Gly Lys Arg Xaa Xaa Lys 225 230 235 240 Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg Arg Gly Gly Xaa Lys Lys Xaa 245 250 255 Arg Arg Xaa Lys Gly Lys Xaa Arg Arg Xaa Lys Lys Xaa Gly Gly Xaa 260 265 270 Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg Xaa Arg Arg Lys Xaa Lys Xaa 275 280 285 Xaa Cys Xaa Gly Tyr Ile Gln Tyr Gly Val Leu Ile Ile Val Ala Val 290 295 300 Ile Ala Leu Arg Ile Val Ile Tyr Val Val Gln Met Leu Ser Arg Leu 305 310 315 320 Arg Lys Gly Tyr Arg Pro Val Phe Ser Ser Pro Pro Gly Tyr Ile Gln 325 330 335 Gln Ile His Ile His Lys Asp Arg Gly Gln Ser Pro Ala Asn Glu Glu 340 345 350 Thr Glu Glu Asp Gly Gly Ser Asn Gly Gly Asp Arg Tyr Trp Pro Trp 355 360 365 Pro Gly Lys Arg Xaa Xaa Lys Xaa Arg Lys Xaa Lys Arg Xaa Xaa Arg 370 375 380 Arg Gly Gly Xaa Lys Lys Xaa Arg Arg Xaa Lys Gly Lys Xaa Arg Arg 385 390 395 400 Xaa Lys Lys Xaa Gly Gly Xaa Cys Xaa Lys Xaa Arg Xaa Lys Arg Arg 405 410 415 Xaa Arg Arg Lys Xaa Lys Xaa Xaa Cys Xaa Gly Ile Ala Tyr Ile His 420 425 430 Phe Leu Ile Arg Gln Leu Ile Arg Leu Leu Thr Arg Leu Tyr Ser Ile 435 440 445 Cys Arg Asp Leu Leu Ser Arg Ser Phe Leu Thr Leu Gln Leu Ile Tyr 450 455 460 Gln Asn Leu Arg Asp Trp Leu Arg Leu Arg Thr Ala Phe Leu Gln Tyr 465 470 475 480 Gly Cys Glu Trp Ile Gln Glu Ala Phe Gln Ala Ala Ala Arg Ala Thr 485 490 495 Arg Glu Thr Leu Ala Gly Ala Cys Arg Gly Leu Trp Arg Val Leu Glu 500 505 510 Arg Ile Gly Arg Gly Ile Leu Ala Val Pro Arg Arg Ile Arg Gln Gly 515 520 525 Ala Glu Ile Ala Leu Leu 530 97 256 PRT Artificial Sequence Description of Artificial Sequence Synthetic peptide 97 Met Gly Ser Asp Met Arg Asp Asn Trp Ile Gln Asn Gln Gln Leu Leu 1 5 10 15 Asn Leu Trp Gly Cys Lys Gly Arg Leu Val Cys Tyr Thr Asn Trp Arg 20 25 30 Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val 35 40 45 Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala 50 55 60 Val Gly Ile Gly Ser Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln 65 70 75 80 Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu 85 90 95 Thr Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu Ala Val Glu 100 105 110 Arg Tyr Leu Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly 115 120 125 Lys Leu Ile Cys Thr Thr Ala Val Pro Trp Asn Ala Ser Trp Ser Asn 130 135 140 Lys Ser Leu Glu Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp 145 150 155 160 Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu 165 170 175 Ser Gln Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp 180 185 190 Lys Trp Ala Ser Leu Trp Asn Trp Phe Asn Ile Thr Asn Trp Leu Ala 195 200 205 Met Glu Lys Tyr Leu Lys Asp Gln Ala Arg Leu Asn Ser Trp Gly Cys 210 215 220 Ala Phe Arg Gln Val Cys His Asp Arg Pro Glu Gly Ile Glu Glu Glu 225 230 235 240 Gly Gly Glu Arg Asp Arg Asp Arg Ser Ile Arg Leu Val Asn Gly Ser 245 250 255 

1. A protein having multiple antigen/epitope sequences for antibodies, wherein the protein is immobilized at a solid phase by at least one binding site, and the antigen/epitope sequences are spaced by bridge compositions in such a way that after binding of the binding site at the solid phase the antigen/epitope sequences are exposed for a binding of the assigned antibodies from the liquid phase.
 2. A protein according to claim 1, wherein a bridge composition is formed by insertion of bridge sequences between two antigen/epitope sequences and/or deletion of a partial sequence between two antigen/epitope sequences arranged in a total sequence.
 3. A protein according to claim 1, wherein the bridge composition is formed by fusion of a bridge sequence with two antigen/epitope sequences.
 4. A protein according to one of the claims 1 to 3, wherein the bridge composition comprises positively charged binding sites for the binding to a negatively charged solid phase, preferably a membrane.
 5. A protein according to one of claims 1 to 4, wherein the antigen/epitope sequences bind different antibodies.
 6. A protein according to one of claims 1 to 5, wherein the antigen/epitope sequences are repetitive sequence elements of identical or different HIV sub-types.
 7. A protein according to one of claims 1 to 5, wherein the antigen/epitope sequences are sequences of different HIV genes and/or strains and/or sub-types.
 8. A protein according to one of claims 1 to 5, wherein the antigen/epitope sequences are sequences of a single HIV sub-type.
 9. A protein according to one of claims 1 to 8, wherein the bridge composition is a sequence element of gp120.
 10. A protein according to one of claims 1 to 9, wherein partial sequences unspecifically binding to antibodies contained in blood are deleted.
 11. The application of a protein according to one of claims 1 to 10 for the production of an immobilizate for the detection of antibodies, wherein first the protein is produced in a dissolved manner, then the protein is bound by at least one binding site to a solid phase, and as an option the solid phase with the protein bound thereto is subjected to at least one rinsing step and/or blocking step.
 12. The application of a protein according to one of claims 1 to 10 for performing a HIV test, wherein an immobilizate according to claim 11 is produced and said immobilizate is placed in a housing, and wherein a detector solution is brought-in in a reaction zone of the immobilizate or is separately added for application to the immobilizate.
 13. A polynucleotide, in particular cDNA, coding for a protein according to one of claims 1 to
 10. 14. An expression vector, preferably plasmide, containing a polynucleotide sequence coding for a protein according to one of claims 1 to
 10. 15. A cell which is transformed by means of an expression vector according claim
 14. 16. A method for the production of a protein according to one of claims 1 to 10, wherein the antigen/epitope sequences and the bridge sequences are selected and the order of the lining-up is defined and DNA coding for the antigen/epitope sequences and for the bridge sequences is subsequently inserted into an expression vector in the defined manner, a cell, preferably E. coli, being transformed by means of the expression vector and transformed cells being selected and cultivated, and wherein the protein expressed from the selected cells is isolated. 